researchA PublicAtion of The ReseaRch InsTITuTe aT naTIonwIde chIldRen’s hospITal

Overseeing Nutritioncutting-Edge, crib-Side Research Accelerates Preemies’ feeding Skills

features

4 Tracking a sugar Thief to shed light on the powers of Streptococcus pneumoniae, Samantha King,

PhD, and her lab are focusing on how these bacteria colonize the airway

and how this colonization leads to disease. Recent research into the

bacteria’s unique ability to modify sugars has led Dr. King’s group to

develop a convicting theory: this bacterium is a thief.

8 Facilitating Feeding through a one-of-a-kind program, Sudarshan Jadcherla, MD, is working to

ensure that perinatal feeding disorders are curbed at the crib side and don’t

continue beyond a baby’s stay in the nicu.

12 a new steroid-sensitive cell?When Richard Ransom, PhD, began his kidney-based research he didn’t

intend to contradict more than 30 years worth of well-accepted theory

regarding kidney disease. Yet that is exactly what he seems to be doing.

extras

7 noteworthy news about the Research institute and its faculty.

16 secondhand smoke signals the response of a young child’s cardiovascular system to secondhand smoke.

on thE covERSudarshan Jadcherla, MD, oversees Noah Braden as he successfully bottle feeds. Through unique crib-side research, Dr. Jadcherla is helping babies (especially those born prematurely) reach one of their most important developmental milestones: feeding orally.

leadeRshIpThe Research Institute at nationwide children’s hospital

John a. Barnard, MdPresident

lauren o. Bakaletz, phdVice President, Basic Sciences Research

Kelly Kelleher, Md, MphVice President, Health Services Research

william e. smoyer, MdVice President, Clinical and Translational Research

Grant Morrow III, MdMedical Director

daniel R. MannVice President, Research Administration and Operations

Katherine s. MilemVice President, Research Business Services

researchWriter and EditorMelissa hamilton

Art DirectorTanya Bender

PhotographersBrad smithdan smith

Manager, Research communicationsJan arthur

contact us at ResearchMagazine@nationwidechildrens.org

research is dedicated to the

mission of informing and inspiring

readers by highlighting scientific

performance at the Research institute

at nationwide children’s hospital.

this publication is produced

biannually by the Marketing and

Public Relations Department at

nationwide children’s hospital.

table of contents

SPRing/SuMMER 2008

research | 3

RIOTM shows that high school girls are more likely to experience a lower extremity injury playing soccer than in eight other sports.*

More than 7 million U.S. high school students are at risk

for becoming a statistic…all because they play a sport.

It’s these sports statistics that Dawn Comstock, PhD,

principal investigator in the Center for Injury Research and

Policy at The Research Institute, focuses on. Dr. Comstock

leads the National High School Sport-Related Injury

Surveillance Study, the only nationally representative

study of U.S. high school sport-related injuries. Certified

athletic trainers from 100 nationally representative U.S.

high schools use an internet-based data collection tool,

RIO™, to prospectively report athletic exposure and injury

data for athletes participating in nine sports (boys’ football,

soccer, basketball, wrestling, and baseball and girls’ soccer,

volleyball, basketball, and softball).

Through RIO™ and evaluation of data from national

emergency department data, Dr. Comstock’s research has

shed light on injury related to rule breaking in sports,

injuries obtained during practice versus in competition,

injury related to wrestling, rugby, soccer, football, martial

arts, ice hockey, lacrosse, field hockey, skating and injury

to knees, ankles, lower extremities, and concussions.

By monitoring patterns of injury and identifying sport-

specific risk factors, the Center for Injury Research and

Policy works to influence targeted, evidence-based

interventions and in turn reduce rates of high school

sport-related injuries.

*Fernandez WG, Yard EE, Comstock RD. Epidemiology of lower extremity injuries among U.S. high school athletes. Acad Emerg Med. 2007 Jul;14(7):641-5.

4 | research

The smeared, black lines spread sporadically across

a thin, paper-like membrane may not look like

much to the untrained eye, but to Samantha King,

PhD, they are the trail of a thief she is spending

her research career trying to catch. As principal

investigator in the Center for Microbial Pathogenesis at The

Research Institute, Dr. King studies Streptococcus pneumoniae,

(pneumococcus), a particularly crafty bacterium responsible for

pneumonia, otitis media, sinusitis, bacteremia and meningitis.

To cause infection, pneumococcus first takes up residence in

the nasopharynx. Yet, this entrance does not always ensure

disease. “Pneumococcus colonizes about 50 percent of people

asymptomatically,” said Dr. King. “Most times, the body will

clear the colonization, but other times it will go on to cause

disease. We really don’t understand how this happens.”

To shed light on the powers of the pneumococcus, Dr. King

and her lab are focusing on how these bacteria colonize body

surfaces and how this colonization leads to disease. Recent

research into the bacteria’s unique ability to modify sugars

has led Dr. King’s group to develop a convicting theory: this

bacterium is a thief.

Tracking a Sugar

ThiefInvesTIgaTIng

BacTerIa’s

sweeT secreT

sTraTegy

Samantha King, PhD

research | 5

Colonization is KeyLike all bacteria, pneumococcus has developed mechanisms

to evade a host’s immune system. One of its most effective

methods is its use of capsules, protective coatings on its exterior

surface. But pneumococcus doesn’t stop at one capsule type for

defense; it enlists 91 capsule types, each structured differently.

Existing preventative measures for pneumococcus infection

include a vaccination strategy targeting these capsules.

However, vaccine effectiveness remains questionable.

“The first marketed vaccine targeted 23 of the 91 capsules, but

it didn’t evoke a good immune response in people most at risk:

the immunocompromised, children under 2 years of age, and

the elderly,” said Dr. King. “There is now a conjugate vaccine

that utilizes a carrier protein and targets seven capsules. It has

been highly effective and has significantly reduced invasive

disease and colonization for those capsule types.”

Yet in the complicated world of infectious disease, success is

not always so simple. “The problem is that although we have

successfully targeted seven capsule types, we have opened the

airway to other capsule types that didn’t used to cause disease

as frequently,” said Dr. King. “We’re changing the pattern of

disease-causing serotypes.”

If science continues to use this capsule-based treatment strategy,

Dr. King envisions a never-ending spiral. “Even if we produce

a vaccine capable of targeting 11 to 13 capsule types, history

is going to repeat itself and it is impossible to create a safe and

effective vaccine with 91 conjugates,” she said.

In addition to the battle with so many capsule types comes the

ever-increasing issue of antibiotic resistance. “This is a classic

organism for antibiotic resistance. Pneumococcus is naturally

transformable; it can take DNA from its environment and

recombine it into its own genome.”

With the obvious need for a new treatment strategy, Dr. King’s

lab has chosen to move away from focusing on how the bacteria

cause disease and move into a more understudied field:

colonization. “Pneumococcus has to colonize the airway before

it can become infectious,” she said. “If we can prevent

colonization, we can prevent disease.”

triCKs of a sugar thiefOne of the greatest mysteries surrounding pneumococcal

colonization pertains to the bacteria’s energy source.

“The pneumococcus is completely dependent on sugars for

growth,” said Dr. King. “Yet, free sugars are at a very low

concentration in the human airway.”

How is it able to survive and grow without its energy source?

Dr. King hypothesizes that pneumococcus steals to survive.

Dr. King’s previous research has shown that pneumococcus

is highly capable of modifying different sugar structures by

producing enzymes that cleave sugar strains found on

surrounding molecules. Moreover, Dr. King’s lab studies

have shown that once pneumococcus has freed sugars from

surrounding molecules, it steals the sugar and uses it as an

energy source.

Even though there are few free sugars in the human airway,

there are plenty of sugar-coated molecules to steal from.

“Basically everything secreted in the human body has sugars on

them,” said Dr. King. “Your airway is covered by epithelial cells

which are covered in sugars; immunoglobulins that protect you

from disease have sugars on them; mucus and the mucin layer

that keeps the airway from getting dry and helps clear away

bacteria are largely composed of sugars.”

Dr. King’s research offers the first evidence of a pneumococcal

survival strategy and provides an experimental basis for

future research.

In addition to a survival strategy, sugar modification also may

provide pneumococcus with an additional defense mechanism.

“Pneumococcus has to colonize the airway before it can become infectious. if we can prevent colonization, we can prevent disease.”

Multiplying Muscle Treatment New Director Joins Center for Cardiovas-cular and Pulmonary Research NIH Clinical and Translational Science Award Benefits Nationwide Children’s

6 | research

“These bacteria are able to colonize for months at a time, so

they must have mechanisms to modify function of host defense

molecules,” she said.

Dr. King also hypothesizes that removing sugars may also allow

the bacteria to burrow through the mucin layer, adhere to the

epithelial surface where they colonize, then move toward the

inner ear. Pneumococcus also may aid in clearing other bacteria

from the airway by stealing their sugar shrouds that usually hide

them from the host’s immune system.

“Our attempt is to get the full picture of how these bacteria mod-

ify sugars and then understand what effect sugar modification

has on its ability to colonize and cause disease,” said Dr. King.

a ThIeF noT yeT convIcTed Although Dr. King’s lab work has shown that pneumococ-

cus manipulates sugars in order to grow, these findings will

ultimately need to be recreated using human samples. As they

learn more in the lab, Dr. King’s group will begin testing their

hypotheses using human epithelial cells and clinical isolates

provided by the Section of Infectious Diseases at Nationwide

Children’s Hospital.

Still, Dr. King says there is much more to learn. “In the long

term, we would like to see this information turned into vaccine

options, but right now, we need to understand to what extent

these bacteria can modify sugars before we can consider using it

as a preventative measure or treatment strategy,” she said.

Even as they work to prove their sugar-stealing hypotheses using

human samples, there will most likely be more obstacles to over-

come. “We suspect that there is a lot of redundancy in the bacte-

ria’s system,” said Dr. King. “Growth is an important function for

bacteria in terms of being able to colonize and cause disease. The

bacteria probably have multiple ways to achieve growth.”

FuTuRe IMplIcaTIons Understanding sugar modification could highlight the powers of

pneumococcus, but at the same time could have larger implica-

tions in the realm of infectious disease. “Other bacteria live in

the human airway and they are going to have to overcome some

of the same problems,” said Dr. King. “By increasing our under-

standing of how pneumococcus colonizes, I’m sure we’re going

to increase our understanding of how other pathogens colonize.”

Dr. King’s research also may shed some light on hemolytic

uremic syndrome (HUS), the most common cause of acute renal

failure in children and a rare effect of pneumococcal infection.

By manipulating sugars found on the surface of red blood cells,

pneumococcus may trigger antibodies that cling to the red

blood cells and ultimately cause a harmful red blood cell cluster.

These clusters could then cause two symptoms associated with

HUS, damage to kidney cells and thrombocytopenia, a decrease

in blood platelets.

As sugar modification and colonization research grows, Dr. King

expects to remain in the forefront. “We are building a foundation

to become world experts in bacteria’s ability to modify sugar,”

said Dr. King, a foundation that could lead to sweet success.

burnaugh AM, frantz lJ, King SJ. growth of Streptococcus pneumoniae on human glycoconjugates is dependent upon the sequential activity of bacterial exoglycosidases. J Bacteriol. 2008 Jan;190(1):221-30.

During early childhood, up to 83

percent of children experience

at least one episode of middle ear

infection, also known as acute otitis

media. Dr. King continues to bring

science closer to an otitis media vaccine

by unlocking the secrets of Streptococcus

pneumoniae, the most common bacterial

agent of these infections. Meanwhile,

other investigators in the center for

Microbial Pathogenesis including lauren

bakaletz, PhD, are targeting the second

most common bacterial cause of otitis

media: nontypeable Haemophilus

influenzae. With assistance from commu-

nity pediatricians, the center is collecting

samples from both healthy children as well

as those with chronic otitis media in an

effort to understand the body’s response to

colonization as well as repeat infection.

Targeting ear Infections

Multiplying Muscle Treatment New Director Joins Center for Cardiovas-cular and Pulmonary Research NIH Clinical and Translational Science Award Benefits Nationwide Children’s

research | 7

noteworthy | thE RESEARch inStitutE At nAtionWiDE chilDREn’S hoSPitAl

Multiplying Muscle investigators in the center for gene therapy have identified the role of a protein that increases muscle size and strength, potentially leading to new clinical treatments to combat musculoskeletal diseases, including Duchenne muscular dystrophy (DMD).

led by brian Kaspar, PhD, these studies focus on a protein called follistatin (fS). using a single injection, gene-delivery strategy involving fS, investigators treated the hind leg muscles of mice. Results showed increased muscle size and strength, quadruple that of mice treated with proteins other than fS. the muscle enhance-ments were shown to be well-tolerated for more than two years. increased muscle mass and strength were also evident when this strategy was tested using a model of DMD.

haidet AM, Rizo l, handy c, umapathi P, Eagle A, Shilling c, boue D, Martin Pt, Sahenk Z, Mendell JR, Kaspar bK. long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci USA. 2008 Mar 18;105(11):4318-22.

Is Bariatric Surgery Best During Adolescence? nationwide children’s hospital has been selected as one of only five institutions nationally to join a multi-institution clinical research study to understand the benefits and risks of bariatric surgery in adolescents.

this longitudinal study called teen-lAbS (longitudinal Assessment of bariatric Surgery) is funded by the national institutes of health. the goal of this observational study is to identify changes in obesity-related health risks in the morbidly obese adolescent population and to compare outcomes to the more traditional adult population undergoing similar surgical intervention. Additional goals of this research are to determine the potential impact on psychosocial impairments related to severe obesity.

teen-lAbS, led by Marc Michalsky, MD, at nationwide children’s, is being conducted in parallel with a study designed to examine similar outcomes in adult patients undergoing bariatric surgical treatment. by comparing features of adolescent and adult bariatric surgery patients, research could help clarify medical and psychologi-cal health outcomes of bariatric surgery. this comparison could lead to better decision-making regarding appropriate timing of surgery for young Americans whose health is increasingly threatened by extreme obesity.

New Director Joins Center for Cardiovascular and Pulmonary Research Pamela lucchesi, PhD, joins the Research institute as director of the center for cardiovascular and Pulmonary Research (previously the center for cardiovascular Medicine).

Dr. lucchesi has an international reputation in cardiovascular research. her research interests focus on oxidant and inflammatory mechanisms of cardiac and vascular disease. She also currently serves as a study section member for both the nih and the AhA and serves on the editorial board of four major cardiovascular research journals.

NIH Clinical and Translational Science Award Benefits Nationwide Children’sin partnership with the ohio State university (oSu) and the oSu Medical center, nationwide children’s hospital will become part of a premier, national consortium funded by the national institutes of health (nih) aimed at transforming clinical and translational research.

in october 2006 the nih launched the clinical and translational Science Awards (ctSA) consortium in an effort to develop a new discipline of clinical and translational research. When fully implemented in 2012, up to 60 institutions will be linked together to energize the discipline of clinical and translational science. ultimately, this consortium will enable researchers to provide new treatments more efficiently and quickly to patients.

Since the program’s inception, only a handful of u.S. health sciences centers have been awarded ctSA grants, with the oSu/nationwide children’s collaboration being one of the few awarded this year. the award totals $34.1 million and is one of the largest grants in the Medical center and the university’s history.

in response to the ctSA grant, nationwide children’s, oSu Medical center and oSu’s seven health Sciences colleges will partner together to create the center for clinical and translational Science (cctS). the cctS will create an environment to administer the ctSA funds and provide additional administrative support and funding opportunities.

Learn about more research news and highlights at NationwideChildrens.org/research.

8 | research

for some babies in the neonatal

intensive care unit (NICU),

eating doesn’t come naturally.

It’s these babies that are most at

risk for lifelong feeding issues

and assisted feeding methods.

That’s why Sudarshan Jadcherla, MD, is

working to ensure that perinatal feeding

disorders are curbed at the crib side and

don’t continue beyond a baby’s stay in the

NICU. As a neonatologist at Nationwide

Children’s Hospital and principal investi-

gator in the Center for Perinatal Research

at The Research Institute, Dr. Jadcherla

is leading the Newborn and Infant

Feeding Disorders Program funded by

a grant from the National Institutes of

Health. This integrated program is the

only one in the world taking a multi-

organ perspective to understand the

development of pediatric feeding

disorders. Through this one-of-a-kind

program, Dr. Jadcherla’s specially designed

research methods are helping babies

become hungry to feed.

FaIluRe To FeedAny infant that fails to eat orally is

considered to have feeding difficulty.

Symptoms of feeding difficulties include

apnea (difficulty breathing), spluttering,

coughing during and after feeds,

regurgitation, failure to coordinate

sucking and swallowing with breathing,

gastroesophageal reflux, irritability and

arching during feeds. These feeding dif-

ficulties can arise from a combination of

gastrointestinal, esophageal, behavioral,

neurological, structural, cardiorespiratory

and metabolic origins.

Yet, no matter the range of symptoms

or causes, the desired objective is the

same. “For every baby diagnosed with a

feeding disorder, the ultimate goal is full

oral feeds,” said Dr. Jadcherla.

Facilitating FeedingcRIB-sIde sTudIes IMpRove BaBIes’ eaTInG haBITs

research | 9

The earlier successful oral feedings begin

the better. When Dr. Jadcherla and his

colleagues began studying the origin of

pediatric feeding disorders, they found

that patients’ feeding issues started very

early in life. In fact, if an infant doesn’t

develop appropriate feeding skills early

on, there is little hope for these skills

to develop later in life. “We can help

children with feeding disorders grow in

other aspects, but we can’t make giant

leaps with their feeding capabilities,”

said Dr. Jadcherla.

So when he decided to pursue his clinical

and research interests, Dr. Jadcherla knew

he would need to focus on perinatal pro-

grams. “We can make the greatest impact

during the first two months of their lives

because this is when the largest trans-

formation is going on in their behaviors

and feeding skills,” he said.

pReMaTuRe BaBIes need specIal caReAs Dr. Jadcherla began trying to identify

the mechanisms of feeding difficulties in

neonates and young infants, he found

that diagnostic methods were limited.

Several techniques had been imported

from applications in older children and

adults, but Dr. Jadcherla questioned the

accuracy and relevance of these methods.

“Healthy adults have well-regulated

neurological systems, including mature

learned behaviors, and they can

regulate their feeding habits in a

conscious manner. On the contrary,

non-verbal babies are still developing

and maturing,” he said.

He also knew that these methods would

be even more complicated for use in the

patient population most at risk for feed-

ing disorders: premature babies. A 2001

study showed that twenty-six percent of

premature babies experience swallowing

dysfunction compared to 13 percent of

the general population of infants.

Many neonates also experience

gastroesophageal reflux disease,

chronic lung disease and neurological

concerns. “Premature babies are even

more vulnerable because their central

and enteric nervous systems are not fully

formed, compared to mature infants,”

said Dr. Jadcherla. “They have swallow-

ing difficulties and often are receiving

intensive care.”

In addition to their underdeveloped

anatomy, premature babies are

frequently on multiple medications,

some of which repress the muscles of the

digestive tract, impair swallowing skills

or airway protection skills. “All of these

skills need to be working in order to help

with feeding,” he said.

Premature babies also have other issues

including neurological diseases and lung

problems all of which Dr. Jadcherla says

play a role in successful feeding. “The gut

interacts with the brain and the brain

interacts with the gut and both interact

with the lungs. There is cross communi-

cation. So, there is a need for integrated

mechanisms to link all of the organs

together and try to come up with the

appropriate strategy.”

seeInG Is BelIevInGThere are multiple ways to scientifically

investigate human diseases such as by

applying research methods to human

tissue samples or by utilizing animal

models. However, to study feeding

difficulties in human infants, Dr.

Jadcherla uses what he considers the

most important model: the human

infant. To properly obtain data regard-

ing babies with feeding concerns, Dr.

Jadcherla’s program utilizes diagnostic

methods safe and effective for use in

babies weighing as few as two pounds.

“Our methods have been peer reviewed,

published and validated, but these

techniques are very hard to do,” said

Dr. Jadcherla. “The babies are so small

that we have to be extra careful. Since

they are in such a fragile state, the babies

have to remain under cardiac monitor-

ing and we closely monitor their vital

signs during testing.” That’s why these

Facilitating FeedingcRIB-sIde sTudIes IMpRove BaBIes’ eaTInG haBITs

Dr. Jadcherla explains the process of his feeding studies to Noah’s mother, Kassie.

feeding studies are conducted at the crib

side, so the babies can receive all of their

usual care without disruption.

In the presence of the nurse and the

patient’s attending neonatologist, Dr.

Jadcherla provides the baby with a

special feeding tube lined with advanced

sensors that can capture the rhythm of

muscular contractions throughout the

aero-digestive tract. Signals are gathered

from the entire pathway including the

mouth and all organs leading to the

duodenum, which is located just beyond

the stomach. These signals are translated

into a graphic form and Dr. Jadcherla

evaluates how these rhythms change.

“We try to understand what is normal

for a particular baby’s feeding and airway

protection skills,” said Dr. Jadcherla.

“Once we understand where the feeding

problems arise, at what level, what mus-

cle groups are involved, we can work to

develop methods to modify outcomes.”

After this diagnostic study is complete,

a team of specialists including an

occupational therapist, nutritionist,

neonatologist, pediatric gastroenter-

ologist, nurse and patient care assistant

provide support for a rational, therapeutic

strategy based on Dr. Jadcherla’s findings

and recommendations. The team then

works with the family to find the best

method for delivering effective nutrition

including, when necessary, the use of

modified feeding strategies.

Dr. Jadcherla says one of the most unique

aspects of this program is that the studies

occur in real time, in real babies. “The

strength of our approach is that there is

no guesswork. Seeing is believing.”

usInG ReseaRch FoR IMpRoved caReThere’s no guessing that Dr.

Jadcherla’s research is capable of

changing babies’ lives.

He recalls a case of a heart transplant

baby who had successful cardiac,

respiratory and neurological outcomes

post-transplant, but couldn’t eat. Her

health care team was considering a

gastrostomy, a procedure in which a

plastic tube is inserted into the

stomach through the abdomen and

used to deliver liquefied food to the

digestive system. However, Dr.

Jadcherla evaluated the baby and

found reflexes that were delayed

and some that were not developed

properly. Her feeding strategy was

modified and after an eight-week

period, she was completely

independent on oral feeds and went

home without needing a gastrostomy.

In fact, a recent landmark study by Dr.

Jadcherla and his team at Nationwide

Children’s showed that these novel

diagnostic methods and multidisci-

plinary feeding strategies were able to

transform 75 percent of babies with

swallowing difficulties into oral feeders,

50 percent of whom didn’t need any

tubes beyond discharge from the

hospital. Aside from the improved

quality of life, this has major cost saving

implications as it has been estimated

that the health care costs for children

on G-tubes is $46,875 for the first year,

almost the cost of one year’s tuition at

Harvard University. As a result of this

study alone, $1.8 million in health care

costs related to G-tubes was avoided.

Not only is Dr. Jadcherla’s research

helping to improve the health of

babies and saving them from invasive,

costly procedures, but it is helping

build a foundation for understand-

ing what is considered “normal” for

premature babies.

As a result of advances in perinatal,

surgical and intensive care, many

immature and sick newborns are

surviving more often than they would

10 | research

a recent landmark study by

dr. Jadcherla and his team

at nationwide children’s

showed that these novel

diagnostic methods and

multidisciplinary feeding

strategies were able to

transform 75 percent of

babies with swallowing

difficulties into oral feeders,

50 percent of whom didn’t

need any tubes beyond

discharge from the hospital.

research | 11

in a recent study, Dr. Jadcherla used a product found

at your local grocery store to examine the mechanisms

of gastroesophageal reflux (gER), a common condition

of prematurity.

babies with gER often experience acidic reflux. Dr.

Jadcherla and colleagues used apple juice made for babies

to mimic the effects of reflux. Apple juice is slightly acidic

and full of vitamin c (ascorbic acid). this approach

allowed them to study the effects acid levels have on the

esophagus and airway protection mechanisms of babies,

such as in episodes of gER.

they found that babies at different ages used different

swallowing mechanisms in order to respond to levels of

acidity in the esophagus. this may be due to the chemical

sensory receptors in the esophagus of younger babies

not recognizing the same ph levels as those in older

babies. this maturation difference could

be one of the reasons for frequent swallowing noted in

younger infants.

Jadcherla SR, hoffmann Rg, Shaker R. Effect of maturation of the magnitude of mechanosensitive and chemosensitive reflexes in the premature human esophagus. J Pediatr. 2006 Jul;149(1):77-82.

have in the past; therefore the field of

perinatal feeding disorders is full of

unknowns. “A premature baby is not

expected to eat independently, but

under those circumstances, what is

normal?” asked Dr. Jadcherla.

To help determine “normal” functioning,

Dr. Jadcherla also performs his motility

studies on healthy premature babies,

those who have had an uncomplicated

neonatal course. So far, he has docu-

mented motility ranges of the esophagus

and the pharynx, but there is much left

to learn.

“We still have not recognized all of the

reflexes involved with feeding. It’s a

very complicated process,” he said.

MoRE AnSWERS nEEDED As Dr. Jadcherla continues to identify

undiscovered reflexes, he will also work

to better understand how feeding and

breathing are related. “The airway

develops from the esophagus

during the first month of embryonic

life and from the primitive gut

develops a long bud which develops

into the lungs. There is an obvious

relationship between the esophagus

and the lungs,” said Dr. Jadcherla.

“Also, the real activity of swallowing

happens in the pharynx and it is very

close to the airway. Therefore, the

relationship between the pharynx

and the airway is critical in order to

develop safe feeding strategies.” He

has received grants from the National

Institutes of Health and the Medical

College of Wisconsin to study this

relationship. He and his team will also

continue to study the long-term effects

of their overall research.

While the need for answers continues

to drive Dr. Jadcherla’s work, he says

he is truly fueled by the belief that his

research could help prevent feeding

problems for babies and children, a

cause that hits close to home.

“I’m greatly inspired by my own

children who were born prematurely,”

said Dr. Jadcherla. “Fortunately, my

children are healthy and doing very

well, but they have taught me what it

means to feed them and what it means

to bring them into good overall growth

and development.”

apple Juice acidity study

Although admittedly unconventional by nature,

Richard Ransom, PhD, principal investigator in the

Center for Clinical and Translational Research at

The Research Institute, doesn’t consider himself to

be a troublemaker. So when he began his kidney-

based research he didn’t intend to contradict more than 30 years

worth of well-accepted theory regarding kidney disease.

Yet that is exactly what he seems to be doing. By investigating

the mechanisms of the kidney’s most specialized cell type, Dr.

Ransom is shedding new light on kidney function and steroid

sensitivity. More importantly, he is searching for new ways to

reverse the damaging effects of steroids, the most commonly

used treatment for kidney diseases.

thE MoSt coMMon chilDhooD KiDnEY DiSoRDER Of all of the conditions negatively affecting the kidneys,

Dr. Ransom’s research focuses on the one most common in

children: nephrotic syndrome. Nephrotic syndrome is a

label for a group of diseases that all cause the kidney filtering

system to leak, and it is one of the first signs of more serious

kidney-damaging diseases.

12 | research

hoW utiliZing StERoiDS in thE lAb coulD

MiniMiZE thE EffEctS of clinicAl StERoiDS

in chilDREn, All bY unEARthing thE PoWER

of thE KiDnEY’S MoSt SPEciAliZED cEll tYPE.

A New Steroid-Sensitive Cell?

Richard Ransom, PhD, shows laboratory steroids and clinical steroids.

Although admittedly unconventional by nature,

Richard Ransom, PhD, principal investigator in the

Center for Clinical and Translational Research at

The Research Institute, doesn’t consider himself to

be a troublemaker. So when he began his kidney-

based research he didn’t intend to contradict more than 30 years

worth of well-accepted theory regarding kidney disease.

Yet that is exactly what he seems to be doing. By investigating

the mechanisms of the kidney’s most specialized cell type, Dr.

Ransom is shedding new light on kidney function and steroid

sensitivity. More importantly, he is searching for new ways to

reverse the damaging effects of steroids, the most commonly

used treatment for kidney diseases.

thE MoSt coMMon chilDhooD KiDnEY DiSoRDER Of all of the conditions negatively affecting the kidneys,

Dr. Ransom’s research focuses on the one most common in

children: nephrotic syndrome. Nephrotic syndrome is a

label for a group of diseases that all cause the kidney filtering

system to leak, and it is one of the first signs of more serious

kidney-damaging diseases.

Children with nephrotic syndrome have faulty filters in

their kidneys. As the body’s blood filtering system, the

kidneys remove excess water, salt and waste products.

Healthy kidneys keep disease-fighting antibodies and

protein in the blood, which helps the blood soak up water

from tissues. But kidneys with damaged filters may leak

protein into the urine causing swelling throughout the body.

Therefore, children diagnosed with nephrotic syndrome have

high levels of protein in their urine, low levels of protein in

their blood, and swelling around their eyes, legs, hands or

stomach. These children also become immunosuppressed

from loss of antibodies into their urine, and become more

susceptible to sometimes fatal, secondary infections. If

protein continues to leak into the urine, parts of the kidney

downstream of the filter become damaged, and this often

leads to end-stage renal disease, a condition that requires

dialysis or kidney transplant.

AMEnDing A 30-YEAR-olD thEoRYThe foundation of nephrotic syndrome theory was developed in

1974 when researcher Robert J. Shalhoub classified nephrotic

syndrome as a disorder of the immune system. Shalhoub

proposed that the overactivity of white blood cells known as

lymphocytes creates a toxin that damages portions of the

kidney making it more permeable to protein. Steroids known

as glucocorticoids have long been used as the primary

treatment for nephrotic syndrome. The Shalhoub hypothesis

maintains that this steroid therapy works because steroids are

deadly to white blood cells.

Although this theory-based treatment has been generally

effective for more than 30 years, Dr. Ransom’s research

findings have revealed possible shortcomings in the

Shalhoub hypothesis. According to Dr. Ransom, there is an

overlooked, steroid-sensitive cell important in nephrotic

syndrome: the podocyte.

PRobing thE PoDocYtE As part of their filtering makeup, the kidneys are comprised of

millions of tiny structures called glomeruli that filter blood from

the urine. Each glomerulus contains a looped blood vessel that

is covered with a layer of cells called podocytes, one of the most

specialized, complex cell types in the human body.

In properly functioning kidneys, podocytes take on a unique

shape. Much like a foot (“pod” is Greek for foot) podocytes have

a large, main body and then fan out to longer, spaced-apart dig-

its. These digits are spread all across the glomerular capillary and

their specialized shape allows for plenty of surface area between

the digits, allowing for rapid filtration of blood.

In cases of nephrotic syndrome, however, the mechanism

that keeps the digits spaced apart is disrupted and the cells

squish together. With this unique shape disturbed, the

filtering surface area changes and protein flows freely through

the glomerulus, out of the kidneys and lost in the urine.

Since changes in the shape of podocytes are directly related

to the symptoms of nephrotic syndrome, Dr. Ransom has

identified this as an important structure for studying the

mechanisms of the disorder. In fact, he believes that the

reason steroid therapy has been successful is, at least in part,

because glucocortocoids work directly to repair the shape and

function of podocytes.

And Dr. Ransom’s preliminary research supports this theory.

When he applied steroids to an isolated podocyte in the

laboratory, the steroids protected the podocyte from damage

and repaired previous injury. These findings begin to question

the Shalhoub hypothesis, which indicates that steroids act only

on white blood cells. Cultured podocytes in the laboratory are

no longer attached to a glomerulus and therefore are no longer

in contact with blood flow or an immune system.

Further research also has provided Dr. Ransom with an idea

of how steroids protect the podocytes. Podocyte foot

processes contain large amounts of a protein called actin

that, as it does in muscles, can form contractile filaments.

When he treated the cultured cells with steroids, the actin

filaments became more resistant to actin-disrupting drugs.

Dr. Ransom believes that steroids may influence the turnover

research | 13

anaToMy oF a podocyTe

as the kidney’s most specialized cell type, podocytes are essential to blood filtra-

tion. Much like a foot, a properly functioning podocyte has a large, main body

and then fans out to longer, spaced-apart digits. The secondary branches of the

digits intertwine with others from adjacent podocytes, spreading all across the

glomerular capillary. Their specialized shape allows for plenty of surface area

between the digits, allowing for rapid filtration of blood. Beneath the podocyte

shown here is the membrane that surrounds the glomerular capillary.

Image courtesy of Smoyer WE & Mundel P, J Mol Med 76:172-183 (1998).

rate of actin filaments which constantly reassemble them-

selves to maintain the podocyte’s “skeleton.” These actin

filaments may also exert force on the underlying capillary

and control the fluid dynamics of the glomerulus. “The

shape of the cell is probably based on its ability to maintain

properly organized actin filaments,” said Dr. Ransom. This is

an important finding considering changes in shape lead to

changes in function, particularly in podocytes, which form

one of the most complex structures of any cell in the body.

bREAKing thE StERoiD cYclE What do these preliminary findings mean for treatment of

nephrotic syndrome? Dr. Ransom hopes they can lead to new

treatments for nephrotic syndrome that have fewer negative

side effects than current steroid therapies.

“The steroid regime these kids undergo is considerable and

steroid therapy has very strong, very unpleasant side effects

for children,” said Dr. Ransom. Steroids can have psycho-

logical effects, can

increase swelling,

affect metabo-

lism and lead to

weight gain, and

can make children

more susceptible

to diabetes and

osteoporosis at an

unusually young

age. Families and

patients can some-

times find these

side effects to be

overwhelming. “I’ve talked to parents who feel that the

effects of the steroids on their kids are worse than the effects

of the disease,” said Dr. Ransom.

After receiving steroids for six to eight weeks, about 80 per-

cent of kids with nephrotic syndrome no longer have protein

in their urine. However, many will later relapse and will be

prescribed stronger doses of steroids to diminish the frequency

and intensity of future relapses. This cycle can continue for

years since the average age of onset for nephrotic syndrome

is 2. Most children will never grow out of the syndrome and

will continue steroid therapy throughout their entire lives,

or will go on to lose kidney function and will require dialysis

and a kidney transplant.

Thanks to a recent grant from the National Institutes of

Health, Dr. Ransom will be able to pursue animal models

of nephrotic syndrome to help clarify the podocyte/steroid

relationship. He plans to create a mouse model that expresses

a highly sensitive steroid receptor only in podocytes. “We’ll

try to affirm our hypothesis that if we give animals lower

doses of steroids, they will be protected only if they have this

mutant, highly sensitive steroid receptor in the podocyte,”

said Dr. Ransom.

Dr. Ransom also plans to join an upcoming study in which a

group of clinicians using steroids to treat nephrotic syndrome

will all modify their treatment strategies at the same time

in the same way. “Surprisingly, at least to a scientist, steroid

therapy can differ between clinicians in regard to dosage

and scheduling regimen,” said Dr. Ransom. This study will

provide a mechanism to accurately compare data of patients

receiving steroid treatment, and will provide important

samples for research.

SticKing With ShAlhoubWhile Dr. Ransom continues to try to improve treatment by

investigating podocytes, other elements of his research continue

on the pathway set forth by Shalhoub’s white blood cell theory.

Some nephrotic syndrome patients do not respond to steroids at

all and their kidneys continue to leak protein despite treatment.

14 | research

“The steroid regime these kids undergo is considerable and steroid therapy has very strong, very unpleasant side effects for children. steroids can have psychological effects, can increase swelling, affect metabolism and lead to weight gain, and can make children more susceptible to diabetes and osteoporosis at an unusually young age.”

Dr. Ransom believes that steroids aren’t effective for these patients because

they may have “faulty” white blood cells that produce too much of a protein

called p-glycoprotein. P-glycoprotein acts as a pump and discharges toxins and

drugs from cells. It also can pump steroids out of cells as well, decreasing their

effectiveness.

Through a multi-center clinical trial, Dr. Ransom and colleagues are collecting

blood samples from patients before they receive steroids and after they

conclude their first course of steroid treatment. They will then evaluate

the role of p-glycoprotein in steroid effectiveness. Do these children have

differing amounts of p-glycoprotein in their white blood cells? Do their white

blood cells produce an overabundance of p-glycoprotein when therapy starts

in order to pump out the substance?

Dr. Ransom says that one of the reasons the work with p-glycoprotein is

exciting is that if children do have elevated levels of this protein, there are

commercially-available, FDA-approved drugs that are known to be inhibitors.

“If we can give a child a low-toxicity drug that inhibits p-glycoprotein which

allows us to give them a tenth as much steroid, that would be a major step

forward,” he said.

This research could also provide a step forward in regard to understanding

the role of podocytes in other diseases. “The health of the podocyte is clearly

critical in diseases that lead to kidney damage such as diabetes and HIV,” said

Dr. Ransom.

Still, Dr. Ransom keeps his current focus in perspective. “The primary goal of this

research is to minimize the effects of steroids in the lives of children,” he said.

Dr. Ransom’s recently published works:Ransom Rf. Podocyte proteomics. Contrib Nephrol. 2004;141:189-211.

Ransom Rf, vega-Warner v, Smoyer WE, Klein J. Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes. Kidney Int. 2005 Apr;67(4):1275-85.

Ransom Rf, lam ng, hallett MA, Atkinson SJ, Smoyer WE. glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int. 2005 Dec;68(6):2473-83.

research | 15

consulting the consortium

As a research scientist in a laboratory

trying to understand the

mechanisms of a human disorder,

Dr. Ransom says it is important that

he gain insight from physicians who

diagnose and treat patients with

nephrotic syndrome. that’s why he is

a member of the Midwest Pediatric

nephrology consortium. co-founded

by faculty at nationwide children’s

hospital, this consortium includes 27

pediatric nephrology programs

throughout the Midwest. Membership

consists of clinicians and research

scientists who share their ideas, current

findings and clinical samples with the

intention of igniting multi-center clinical

and translational research into childhood

kidney diseases.

“since my focus is trying to understand the basis for a real phenomenon, why therapy works, what the disease is doing, I feel fortunate in being associated with the consortium,” said dr. Ransom. “It puts me in contact with clinicians across the country who recognize the importance of research for advancing clinical treatment.”

“The steroid regime these kids undergo is considerable and steroid therapy has very strong, very unpleasant side effects for children. steroids can have psychological effects, can increase swelling, affect metabolism and lead to weight gain, and can make children more susceptible to diabetes and osteoporosis at an unusually young age.”

nonPRofit oRg.

u.S. PoStAgE

paId

coluMbuS, oh

PERMit no. 777700 children’s Drivecolumbus, ohio 43205-2696

Judith Groner, MD, and collaborators in the

Center for Cardiovascular and Pulmonary

Research have conducted the first study to

examine the response of a young child’s

cardiovascular system to secondhand smoke.

According to the study, children ages 2 to 5

absorbed six times more nicotine than

adolescents ages 9 to 14 from the same level

of parental smoking. Toddlers in the homes of

smokers not only had higher levels of nicotine,

but also had higher levels of markers for

cardiovascular disease.

Presented at the American heart Association’s 48th Annual conference on cardiovascular Disease Epidemiology and Prevention.

2013

Secondhand Smoke Signals