So you want to write a grant?

1. So you want to write a grant?

2. Edwin L. Bierman, M.D.

3. So You Want to Write a Grant? • What is my topic? • Who is my audience? • When is the deadline? • What are my chances? • What now?

4. Get Assistance • Colleagues • Mentors • Department chairs • Deans and associate deans • Grants and Contracts offices • Specific funding agencies • grantdoctor@aaas.org

5. Significance • Choose your area of research pursuit carefully! • Is it relevant to human health/disease? • Why is your idea important? • Make a compelling case • What will be different if your specific aims are fulfilled? • Will both science and people benefit? • If the work is basic, don’t overstate the clinical significance

6. Innovation • Establish the need in Background and Significance • How will what you’re doing improve on what is already known? • strategies, methods, interventions • Avoid PAIDS, the ‘Paralyzed Academic Investigator’s Disease Syndrome’!!! • Goldstein JL, J Clin Inv 78: 848-854, 1986

9. PAIDS • Particularly common among clinical M.D. investigators • Doesn’t spare the most intelligent, curious, and ambitious • Typically occurs early in the independent phase of career development • Often is manifested by repetitive experiments in an alternative system • What’s really new here?

10. PAIDS AVOIDANCE • Basic science training • Technical courage • Important questions • New techniques • Avoid fossilization in what we already know, e.g. • Michael Brown and Joseph Goldstein • familial hypercholesterolemia • LDL receptor mutations

11. Hypotheses and Specific Aims • Focus, focus, focus! • Be as mechanistic as possible • Avoid being too ambitious • Limit number • 2-4 are best • All should be related, but • Don’t build one specific aim on previous aims

12. Preliminary Data • Sufficient to make grant feasible, but not excessive or irrelevant • You have the gene/antibody/mouse/population • Be objective • Be graphic • Figures/Tables should be able to stand alone • in proximity to relevant text • Prove techniques are available and/or collaborations are in place • Letters are essential here!

13. Experimental Plan • Repeat Hypotheses/Specific Aims with accompanying Rationale • Make no assumptions that reviewers know how you intend to proceed • Justify sample size and analytical approach • Avoid excessive detail for methods • Except for novel use of complex technologies • Refer to relevant publications • your’s or a collaborators’, if possible • Identify pitfalls and provide alternative strategies if/when problems do arise • Provide a timeline

14. Budget • Clarify • Justify • In detail • Carefully consider % effort • Avoid ‘to be named’ • Don’t ‘pad’ • Science drives the request

15. Abstract • Not an afterthought • Longer ‘shelf life’ than the rest of the application • Sets the stage • One page advertisement • Content • Brief background • Hypotheses/Specific aims • Significance • Fill the box!

16. Style • Critically important for readership • Use #11 or 11.5 font size • Keep paragraphs brief • Use graphs/figures when possible • Spacing! • Bold, italics and underliningprovide needed emphasis • Strategies for each • Be consistent!

17. 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.

18. Before Your Grant is Submitted/Reviewed • Read, reread and read again! • Don’t rely on spell-check only • Get input • Former mentor • Informed colleague • Outside reader • Human subjects, vertebrate animals • Resources and environment • Address all aspects of the application • Submit supplemental materials before deadline

19. Human Subjects • Why not animals? • Safety, safety, safety! • Women, minorities, children • Exclusions must be scientifically based • IRB approval

20. Revised Applications • Wait weeks after review is received to respond • Acknowledge and respond to each criticism/comment • Rebut only if • You’re certain a reviewer is wrong • You have new data • Remember, triaged applications can be funded the next round • Address in detail ‘fatal flaws’

21. GrantApplication A good scientist is always pushing the envelope.

22. Best wishes in all of your pushing!