David A Schwartz Basic Elements of NIH Grants https grantsnihgovgrantsgrantsprocesshtm Specific Aims Research Strategy Significance Innovation Approach Specific Aims Overall goal excitement ID: 1000617
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1. Writing a Persuasive Grant ProposalDavid A. Schwartz
2. Basic Elements of NIH Grants[https://grants.nih.gov/grants/grants_process.htm]Specific AimsResearch StrategySignificanceInnovationApproach
3. Specific AimsOverall goal (excitement)Importance of research (why?)Preliminary data (why you?)Hypothesis (innovation - multidimensional)Specific aims (plan)Impact (so what)
4. Overall goal – understandable/excitingImportance of research Preliminary data (why you?)
5. Problem to be solved and potential solutionNovelty/InnovationHypothesis – multidimensional (makes reviewer think [but not too much])
6. Characteristics of a Sound HypothesisHypothesis must be:Grounded in existing knowledge and theoriesExpresses a relation between measurable variables (cause-effect with a temporal relationship) Unambiguous and novelFeasible and amenable to testingYou are addressing an unmet need (be explicit)
7. Simple and understandable specific aimsState-of-the-art science (collaboration)Independent but progressive/dependent knowledgeImpact of work
8. Reviewer Response to Specific Aims?Excited about the workUnderstands the importance of your proposalKnows you can do it and are uniquely qualifiedRecognizes innovation of hypothesisThinks that the plan is feasibleKnows that successful completion of your proposal will have an impact on the fieldReviewer becomes an advocate of your work and hasn’t work too hard to understand your perspective
9. SignificanceImportance of the problem Critical barrier to progressImprove knowledgePreliminary resultsEnd with impact
10. Content expertiseShort (1-2 pages)User friendlyImpact/deliverable
11. Reviewer Response to Significance?You know this stuffRigor and scientific premiseYou have perspective and understand the context of your work (acknowledge others)You’ve contributed to in a meaningful wayYour proposal will have an impact on the fieldReviewer is awake, alert, understands the context, and is an even stronger advocate of your work
12. InnovationShift current research paradigmNovel concepts, approaches, or interventions (preliminary results)Application of innovation/results
13. Our proposed research has the potential of changing our basic concepts about asthma. Despite major investments that have been made in asthma research over the past two decades, the disease remains a major public health problem that paradoxically is increasing in prevalence, incidence, and severity. While we know that inheritance (non-Mendelian genetics), parent-of-origin, environment, and in utero exposures play important roles in the etiology of asthma, there is no well developed unifying mechanism accounting for these etiologic events/triggers. Although the Hygiene Hypothesis is appealing conceptually (10) and ties a number of these basic etiologic events together, there are several competing hypotheses (T cell skewing, infection, diet, obesity, etc.), and none of these hypotheses fully account for the complex interaction between host and environmental determinants of asthma. However, the prevalence of atopy and asthma are not concordant, allergic mechanisms account for only 50% of asthma cases, very high asthma rates are present in some countries, such as Latin America, where the hygienic conditions are less than ideal, and although the prevalence and incidence of asthma continue to increase in inner cities in the U.S., it is unlikely that housing conditions in these communities are becoming more hygienic. While epigenetic mechanisms not only provide a unique cause of asthma, these basic transcriptional controls potentially serve to explain some of the prevailing hypotheses underlying the development of asthma. So while epigenetic mechanisms have the potential of changing our basic concepts about asthma, these mechanisms may not only account for the etiologic events/triggers related to asthma but may also help to explain some of the prevailing hypotheses attributed to this disease.
14. Our proposed research in epigenetics has the potential to transform asthma therapy from palliative to preventive, and may alter our recommendations for pregnant women throughout the world. Currently, other than avoidance of cigarette smoke, we are simply unable to prevent asthma. Most patients with asthma rely on chronic medications to reduce the severity of their symptoms. Understanding the importance of epigenetic mechanisms in the development of asthma and the periods of vulnerability in establishing epigenetic marks, has the potential of preventing the development of this disease, not only in our offspring but in their children as well. Our observations in mice (11) suggest that the increased prevalence of allergic asthma in humans may, in part, be related to increased perinatal dietary supplementation with methyl donors, such as folate. In fact, the asthma epidemic in developed countries coincides with worldwide recommendations to enhance periconceptional folate supplementation. Moreover, recent epidemiologic evidence from a birth cohort of 32,077 Norwegian children suggests that perinatal folic acid supplements are associated with an increased risk of wheeze at 18 months of age (45). Given the importance of folate supplementation in preventing congenital abnormalities and the differences in murine and human biology, we need to carefully consider the potential for adverse consequences of dietary supplementation during pregnancy before considering any modifications to the current recommendations. Our research (11), as well as that of others (45), however, suggests that too much dietary supplementation, especially with methyl donors during pregnancy, may have unexpected biological and pathophysiological consequences. Understanding the complex interactions between in utero exposures and epigenetic vulnerability will provide insight into future interventions for individuals at risk for the development of allergic asthma and may lead to the prevention of this disease altogether.
15. Our proposed research in asthma epigenetics may prove important in other immune and autoimmune diseases, especially those that are increasing in prevalence and severity in developed countries. In fact, over the past three decades, in addition to asthma, developed countries have also experienced an increasing incidence of other immune/autoimmune diseases such as atopic dermatitis, multiple sclerosis, insulin-dependent diabetes mellitus (type I diabetes), and Crohn’s disease (49). While environmental exposures and access to healthcare may account for some of these differences, one needs to seriously consider whether differences in diet, especially during gestation, and unique exposures affecting epigenetic mechanisms may be contributing to the development and uneven geographic distribution of these immune and autoimmune conditions. There are several unique aspects of our project that distinguish it from previous studies and serve to enhance the impact of our proposed research. First, genome-wide DNA methylation profiling has not yet been undertaken on a large scale within the context of asthma. Second, the populations available to us provide unique opportunities not only to characterize the epigenetic determinants of asthma, but also to assess the ways in which these marks are transmitted between generations (parent-of-origin effects), and modified by known environmental determinants (such as exposure to a farming environment). Third, the wealth of genome-wide expression and genotypic data that is available for our primary cohort means that we will be able to integrate known genetic risk factors into our investigation, and undertake the world’s first genome-wide analysis of methyl-eQTL (expression Quantitative Trait Loci); highlighting which CpG islands appear to moderate gene expression through their methylation status. This resource will clearly be of great relevance to the wider scientific community.
16. Reviewer Response to Innovation?More excitement about your workUnderstands how your work creates a new future for your fieldLikes the way you and your colleagues thinkBe Bold: the reviewer needs to know you are on the cutting edge of your chosen field
17. ApproachOverall strategyRigor of experimental designGeneral methodsSpecific methods (preliminary results)Problems/alternative approaches
18. Remind the reviewer about your proposalTell the reviewer how it all fits togetherShow the reviewer how it all fits together
19. Aim 3: Confirm Epigenetic TargetsAim 4: ImprintingValidationDerivationConfirmationAim 2: Airway Epithelia and PBMCsAim 5: Case ControlMurine Lung DNA MethylationAim 1: Discordant Sibling Pairs
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26. Reviewer Response to Approach?Makes senseInspires confidenceState-of-the-art methodsConsidered alternativeThe reviewer believes you can do it, you’re grounded in reality, and you’ve engaged the experts
27. Actively Seek AdviceRead someone else’s funded proposalDevelop a mentorship committee of established investigators and include letters of supportTalk with NIH program officers