So you want to write a grant?

Edwin L. Bierman, M.D.

So You Want to Write a Grant?

What is my topic?What is my topic? Who is my audience?Who is my audience? When is the deadline?When is the deadline? What are my chances?What are my chances? What now?What now?

Get Assistance ColleaguesColleagues MentorsMentors Department chairsDepartment chairs Deans and associate deansDeans and associate deans Grants and Contracts officesGrants and Contracts offices Specific funding agenciesSpecific funding agencies grantdoctor@aaas.orggrantdoctor@aaas.org

Significance Choose your area of research pursuit Choose your area of research pursuit

carefully!carefully! Is it relevant to human health/disease?Is it relevant to human health/disease?

Why is your idea important?Why is your idea important? Make a compelling caseMake a compelling case

What will be different if your specific What will be different if your specific aims are fulfilled?aims are fulfilled? Will both science and people benefit?Will both science and people benefit? If the work is basic, don’t overstate the If the work is basic, don’t overstate the

clinical significanceclinical significance

Innovation Establish the need in Background and Establish the need in Background and

SignificanceSignificance How will what you’re doing improve on How will what you’re doing improve on

what is already known?what is already known? strategies, methods, interventionsstrategies, methods, interventions

Avoid PAIDS, the ‘Avoid PAIDS, the ‘Paralyzed Academic Paralyzed Academic Investigator’s Disease SyndromeInvestigator’s Disease Syndrome’!!!’!!! Goldstein JL, Goldstein JL, J Clin InvJ Clin Inv 78: 848-854, 1986 78: 848-854, 1986

PAIDS Particularly common among clinical M.D. Particularly common among clinical M.D.

investigatorsinvestigators Doesn’t spare the most intelligent, curious, Doesn’t spare the most intelligent, curious,

and ambitiousand ambitious Typically occurs early in the independent Typically occurs early in the independent

phase of career developmentphase of career development Often is manifested by repetitive Often is manifested by repetitive

experiments in an alternative systemexperiments in an alternative system What’s really new here?What’s really new here?

PAIDS AVOIDANCE Basic science trainingBasic science training Technical courageTechnical courage

Important questionsImportant questionsNew techniquesNew techniquesAvoid fossilization in what we already Avoid fossilization in what we already

know, e.g.know, e.g.Michael Brown and Joseph GoldsteinMichael Brown and Joseph Goldstein

• familial hypercholesterolemiafamilial hypercholesterolemia–LDL receptor mutationsLDL receptor mutations

Hypotheses and Specific Aims Focus, focus, focus!Focus, focus, focus! Be as mechanistic as possibleBe as mechanistic as possible Avoid being too ambitiousAvoid being too ambitious Limit numberLimit number

2-4 are best2-4 are best All should be related, butAll should be related, but

Don’t build one specific aim on Don’t build one specific aim on previous aimsprevious aims

Preliminary Data Sufficient to make grant feasible, but not excessive Sufficient to make grant feasible, but not excessive

or irrelevantor irrelevant You have the gene/antibody/mouse/populationYou have the gene/antibody/mouse/population

Be objectiveBe objective Be graphicBe graphic

Figures/Tables should be able to stand aloneFigures/Tables should be able to stand alone in proximity to relevant textin proximity to relevant text

Prove techniques are available and/or Prove techniques are available and/or collaborations are in placecollaborations are in place Letters are essential here!Letters are essential here!

Experimental Plan Repeat Hypotheses/Specific Aims with accompanying Repeat Hypotheses/Specific Aims with accompanying

RationaleRationale Make no assumptions that reviewers know how you Make no assumptions that reviewers know how you

intend to proceedintend to proceed Justify sample size and analytical approachJustify sample size and analytical approach Avoid excessive detail for methodsAvoid excessive detail for methods

Except for novel use of complex technologiesExcept for novel use of complex technologies Refer to relevant publications Refer to relevant publications

your’s or a collaborators’, if possibleyour’s or a collaborators’, if possible Identify pitfalls and provide alternative strategies Identify pitfalls and provide alternative strategies

if/when problems do ariseif/when problems do arise Provide a timelineProvide a timeline

Budget ClarifyClarify JustifyJustify

In detailIn detail Carefully consider Carefully consider % effort% effort Avoid ‘to be named’ Avoid ‘to be named’ Don’t ‘pad’Don’t ‘pad’

Science drives the requestScience drives the request

Abstract Not an afterthoughtNot an afterthought

Longer ‘shelf life’ than the rest of the Longer ‘shelf life’ than the rest of the applicationapplication

Sets the stageSets the stage One page One page advertisementadvertisement

ContentContent Brief backgroundBrief background Hypotheses/Specific aimsHypotheses/Specific aims SignificanceSignificance

Fill the box!Fill the box!

Style Critically important for readershipCritically important for readership Use #11 or 11.5 font sizeUse #11 or 11.5 font size Keep paragraphs briefKeep paragraphs brief Use graphs/figures when possibleUse graphs/figures when possible Spacing!Spacing! BoldBold, , italics italics and and underliningunderlining provide provide

needed emphasisneeded emphasis Strategies for eachStrategies for each Be consistent!Be consistent!

SPECIFIC AIM #1: TO DEFINE THE ROLE OF LPL IN THE PERIPHERAL NERVOUS SYSTEM.

 

Rationale and Hypotheses: Unequivocally, the only definitive way to determine whether or not LPL activity and/or enzyme protein in Schwann cells is important to the biology of the PNS in vivo is to genetically eliminate the lipase (P0 LPL -/-) and replace it with a catalytically inactive form of the enzyme (P0 LPL */-). In LPL mutant mice, changes in nerve function and myelin content can be assessed. To further determine the role of the lipase, the response of the peripheral nerve to nerve-crush injury will be assessed. It is expected that deficiency of the active lipase, but not the enzyme protein, will result in reductions in both myelination and nerve conduction velocity, with a delayed response to nerve-crush injury. In vitro, neurons from Schwann cell replete mice (LPL +/+), P0 LPL -/- and P0 LPL */- will be examined to determine their ability to grow and sprout processes. Moreover, in primary Schwann cells from mice with Schwann cell specific knockouts of LPL (P0 LPL-/-), there will be a reduction in myelination when co-cultured with dorsal root ganglion neurons. In mice with a knock-in of the catalytically inactive lipase (P0 LPL */-), it is hypothesized that the defect in myelination in vitro will also be largely eliminated. This effect will relate to the ability of the inactive lipase to bind and internalize lipoprotein particles, and thereby provide fatty acids for myelin lipid synthesis.

 Experimental Approaches:  

A.     Generation of Schwann cell specific LPL knockout (P0 LPL-/-) mice.

  To generate P0 LPL-/- mice, inactivation of LPL will be achieved by using the cre-loxP DNA recombination method, where the cre recombinase carries out the site-specific DNA recombination at a specific 34-bp sequence called loxP. When cre recombinase is introduced into cells that have genomic DNA flanked with two properly oriented loxP sites, the genomic DNA flanked by the two loxP is cleaved out. Therefore, LPL flox/flox mice, provided by Dr. Ira Goldberg (see letter), will be mated with heterozygous P0-cre mice (Dr. I. Parada) that express the cre recombinase specifically in Schwann cells (Phase 1). Identification of all mice will use PCR from tail tip DNA and primers specific for the cre transgene, the floxed LPL and the deleted LPL alleles. Confirmation of all mice will also include measurements of LPL mRNA by in situ hybridization and immunohistochemistry.

Before Your Grant is Submitted/Reviewed

Read, reread and read again!Read, reread and read again! Don’t rely on spell-check onlyDon’t rely on spell-check only

Get inputGet input Former mentorFormer mentor Informed colleagueInformed colleague Outside readerOutside reader

Human subjects, vertebrate animalsHuman subjects, vertebrate animals Resources and environmentResources and environment

Address all aspects of the applicationAddress all aspects of the application Submit supplemental materials before deadlineSubmit supplemental materials before deadline

Human Subjects Why not animals?Why not animals? Safety, safety, safety!Safety, safety, safety! Women, minorities, childrenWomen, minorities, children

Exclusions must be scientifically Exclusions must be scientifically basedbased

IRB approvalIRB approval

Revised Applications Wait weeks after review is received to respondWait weeks after review is received to respond Acknowledge and respond to each Acknowledge and respond to each

criticism/commentcriticism/comment Rebut only ifRebut only if

You’re certain a reviewer is wrongYou’re certain a reviewer is wrongYou have new dataYou have new data

Remember, Remember, triagedtriaged applications can be funded applications can be funded the next roundthe next round Address in detail ‘Address in detail ‘fatal flaws’fatal flaws’

Grant Application

A good scientist is always pushing the envelope.

Best wishes in all of your pushing!