Research Strategy – Significance Why is your research important?

1. Research Strategy – SignificanceWhy is your research important? Marc R. Moon, M.D. Joseph C. Bancroft Professor of Surgery Division of Cardiothoracic Surgery & Center for Diseases of the Thoracic Aorta Washington University School of Medicine St. Louis, Missouri AATS Grant Writing Workshop, March 2011

2. Research Strategy – SignificanceStructure of the Proposal • Text of a grant: • Specific Aims - Statement of the problem (introduction) • Significance (includes background) (1-2 pages) • Innovation (½ page) • Approach – how the problem will be solved • Start with general overview of the plan / team (optional) • Address each Specific Aim – • preliminary / progress data, experimental plan, anticipated results / potential problems (limitations) / alternative approaches

3. Research Strategy – Significance Structure of the Proposal • Virtual “Page 1” is most important - Hypothesis-driven: • Introductory paragraph - Significance • Specific Aims • Hypotheses • Develop hypotheses and state them clearly (and significance) • Specific Aims : • Outline a reasonable number to address the hypotheses • Aims should represent a prediction than can be tested experimentally • Be focused – don’t take on too much

4. Research Strategy – Significance Why is your research important? • Introduction to Specific Aims: • Catch the reviewers attention – significance of grant • Start with broad, long-range, often grand objective • Not necessarily achievable within the time-frame • Then focus on more short-term goals and how these are essential to ultimately solve long-term goals • Ties current proposal to your previous work • Specific Aims must be achievable in the proposed time-frame

5. Research Strategy – SignificanceWhy is your research important? • Introduction to Specific Aims: • First place to describe significance • “There is a significant problem or unknown with a critical need to solve, and solving this problem is aligned with the mission of the funding agency.” (Y. Colson) • 3-4 key facts – critical problem with significance to the society and funding agency PPH, which most often afflicts young, otherwise healthy young women is incurable and culminates in RHF and death in the majority of patients, but the molecular and biomechanical mechanisms responsible for the progression from compensated to decompensated failure remain unknown.

6. Research Strategy – SignificanceWhy is your research important? • Introductory Paragraph: • Show them you are competent • What makes you (and your co-investigators) unique? • How will your unique skill set permit you to complete this important work? Since 1999, our laboratory has had as its focus: 1.) Characterization of A, 2.). Determination of B, and 3.) Mechanistic confirmation of C. Having built this solid methodologic foundation, consisting of novel techniques to assess D, we now have the unique ability to … This will facilitate completion of the studies outlined in this proposal, designed to address the following Specific Aims:

7. Research Strategy – SignificanceWhat makes a topic significant? • It impacts a large number of people with substantial consequence CPH develops in 60% of patients with COPD, including emphysema and chronic bronchitis, diseases that affect over 16 million American today and claimed more than 120,000 lives in 2002. Apicomplexa are important human pathogens responsible for numerous severe diseases around the World. These include the various forms of malaria, as well as opportunistic infections associated with AIDS (which impacts over one million Americans and has claimed over 500,000 lives). Boris Striepen, Ph.D., University of Georgia National Institute of Allergy and Infectious Disease, 2011

8. Research Strategy – SignificanceWhat makes a topic significant? • Someone important says it is significant - Politician “We can, and we will do more to better treat this devastating disease.” U.S. Senator John Cornyn (R-Texas) October 8, 2004 – Floor of the U.S. Senate In 2004, the Disease X Research Act was introduced to “expand, intensify, and coordinate” the activities of the NHLBI with respect to research on Disease X. Senator Cornyn emphasized that, “This important bill has the potential to help tens of thousands of Americans and their families who are struggling with Disease X.”

9. Research Strategy – SignificanceWhat makes a topic significant? • Someone important says it is significant – Respected clinician / Researcher Dr. Robyn Barst, a renowned clinician in the field, confessed: “Unfortunately, despite the demonstrated efficacy of [new treatment options], … we often are only delaying an inevitable fatal outcome for many patients.” Dr. Stuart Rich, a renowned investigator in the field, concluded emphatically in a recent editorial that, “Atrial septostomy needs to be studied further as an alternative treatment… when no other option exists.”

10. Research Strategy – SignificanceWhat makes a topic significant? • Know your audience – review the committee roster • AATS (http://www.aats.org) • Research Scholarship Committee • TSFRE (http://www.tsfre.org) • Research Committee • NIH: • Center for Scientific Review (http://cms.csr.nih.gov) • Office of Extramural Research (http://era.nih.gov/roster)

11. Research Strategy – SignificanceWhat makes a topic significant? • Someone important says it is significant – Committee member Dr. L. Henry Edmunds, the immediate past Chairman of the NIH Surgery and Bioenginnering Study Section, wrote in his 1997 textbook Cardiac Surgery in the Adultthat “… ischemic mitral regurgitation is an extremely common complication of MI. The incidence of IMR in the United States is estimated to be 1.2 to 2.1 million patients … with a 1-year mortality of 17 to 40 percent.” These data indicate that IMR is a common problem, but underappreciated.

12. Research Strategy – SignificanceWhat makes a topic significant? • An important organization says it is significant The House of Representatives identified Disease X as an “Item of Interest” in the FY2011 budget. • As outlined in the World Health Organization Executive Summary, essential areas for research include: • What are the mechanisms responsible for … • What is the optimal timing of… The American College of Chest Physicians Consensus Statement inauspiciously admits: “There is no cure for Disease X, nor is there a therapeutic approach which is uniformly accepted or successful.”

13. Research Strategy – SignificanceWhat makes a topic significant? • Make sure the organization to which you are applying considers the organization you are quoting to be important • Funding agencies generally do not care about the goals, objectives, or strategic plan of other funding agencies The mechanisms responsible for the progression of Disease X and its treatment are recurring themes throughout the NHLBI Strategic Plan for the years FY 2001-2005.

14. Research Strategy – SignificanceWhat makes a topic significant? • FOA: Funding Opportunity Announcement • Identify areas of increased priority and/or emphasis • May be sponsored by one or more NIH institutes. • PA: Program Announcements • RFA: Requests for Applications • PAs may or may not have set-aside funds. If not, some applications are funded beyond the payline. RFAs always have set funds. • PAs are usually broader: • PA may focus on biodefense research opportunities – RFA will focus on developing therapies for a particular disease • Applications in response to a PA are not reviewed together – go to study section with the best match. RFAs are reviewed together.

15. Research Strategy – Significance Writing the Significance section • Significance and Innovation • Avoid jargon • Make it understandable to all (write science for the clinicians, and write clinical aspects for the scientists) • Logical, clear compelling argument • Why the proposed study is necessary • Highlight “Gaps” in knowledge and how your project addresses the gaps • How it differs from previous work • Specific ways it is innovative

16. Research Strategy – Significance Writing the Significance section • SF424 (R&R) Application Guide for NIH • http://grants.nih.gov/grants/forms.htm • Significance / Innovation / Approach (12 pages) • (a) Significance • Explain the importance of the problem or critical barrier to progress in the field that the proposed project addresses. • Explain how the proposed project will improve scientific knowledge, technical capability, and/or clinical practice in one or more broad fields. • Describe how the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field will be changed if the proposed aims are achieved.

17. Research Strategy – Significance Writing the Significance section • Multiple Specific Aims • http://grants.nih.gov/grants/forms.htm • A combination of both is appropriate If an applicant has multiple Specific Aims, then the applicant may address Significance, Innovation and Approach for each Specific Aim individually, or may address Significance, Innovation and Approach for all of the Specific Aims collectively.

18. Research Strategy – Significance Writing the Significance section • Significance section includes background: • Summarize important results outlined by others • Know your audience – Check study group members for publications • Critically evaluate existing knowledge  tell us what is missing. • Answer 3 questions: • What is known? • What is not known? • Why is it essential to find out?

19. Research Strategy – SignificanceWriting the Significance section • Health Relevance • Congress appropriates NIH funds with the goal of finding solutions to important public health problems • Discuss health relevance – specifically towards the disease processes the organization studies (AHA – cardiovascular) • Reviewers will discuss the health impact of your project • Scientific Relevance • The best proposals describe how they will increase both scientific knowledge and improve health

20. Research Strategy – SignificanceWriting the Significance section • Background / Significance: • Identify gaps (contradictions in previous studies) and describe how they will be filled by this project • Convince us that these gaps are important • Do not be one-sided on controversies • Three Goals: • Justify the line of investigation (significance) • Establish competence of investigator • Educate a reviewer who is unfamiliar with you and topic

21. Research Strategy – SignificanceWriting the Significance section • Start with a general significance statement (organization & expert): • Follow with some background, and a gap statement: The NIH is committed to translating basic biomedical research into clinical practice and thereby impacting global human health,1 and Francis Collins identifies high-throughput technology as one of five areas of focus for the NIH’s research agenda. 2 For many diseases, researchers have identified successful novel therapeutics or research probes by applying technical advances in automation to high-throughput screening (HTS) using either biochemical or cell-based assays. However, the molecular mechanisms of many diseases that deeply impact human health worldwide are not well-understood and thus cannot yet be reduced to biochemical or cell-based assays. Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

22. Research Strategy – SignificanceWriting the Significance section • Significance – Organization (NIH PA) • Authoritative expert opinion related to planned experimentation Enabling high throughput screening (HTS) in whole organisms is recognized as a high priority (NIH PA-08-024). The bottleneck that remains for tackling important human health problems using C. elegans HTS is image analysis (NIH PA-07-320). It has been recently stated, “Currently, one of the biggest technical limitations for large-scale RNAi-based screens in C. elegans is the lack of efficient high-throughput methods to quantitate lethality, growth rates, and other morphological phenotypes”. Our proposal to develop image analysis algorithms to identify regulators of infection and metabolism in high-throughput C. elegans assays would bring image-based HTS to whole organisms, and have the following impact: Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

23. Research Strategy – SignificanceWriting the Significance section • Background / Significance: • Integrate your previous findings within the background – show reviewers the relevance of your previous contributions • Bridge your hypotheses and long-term objectives to the background review (and ideally your previous work) For some diseases, unique mechanisms of action may be necessary to break new therapeutic ground. Our work recently identified six novel classes of chemicals that cure model organisms … through mechanisms distinct from directly killing the bacterium itself. Manipulation of C. elegans may yield clinical cures. Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

24. Research Strategy – SignificanceBackground / Competence • Previous methodology development and mechanistic investigation • From other investigators: • From your own laboratory: Altered levels of SERCA have been found in monocrotaline-treated rats, … We have developed a technique to assess A, which, to the best of our knowledge, is a novel approach. Preliminary studies outline our unique methodology which is necessary to study …

25. Research Strategy – SignificanceBackground / Competence • From your co-investigators: • From your institution: Co-investigator, Dr. X, has previous reported receptor X upreguation and enhanced Ca2+ release from the SR in ischemia and hypoxia. Our preliminary studies demonstrate a similar change in Disease Y, which we hypothesize represents the mechanism responsible for the progression from compensated to decompensated failure (hypothesis 1.3). The Wash U approach, analyzing high-speed tissue-tagged MRI images in real-time, has provided novel insights into the pathogenesis of Disease X. In the current proposal, we plan to use this well-developed methodology to identify the mechanistic precursor of Disease Y (Hypothesis 2.1).

26. Research Strategy – SignificanceBackground / Competence • Peer-reviewed validation of the importance of your line of research • Awards and Honors: • Foundation “Starter” Grants: It is noteworthy that our preliminary investigation of the impact of CPH on expression of calcium-handling proteins by Dr. X, postdoctoral research fellow, won the prestigious American College of Cardiology Young Investigator Award, reflecting the translational importance of this line of investigation. The development of our unique methodologic approach was supported by a research grant from the Thoracic Surgery Foundation for Research and Education.

27. Research Strategy – SignificanceCompetence / Knowledge Gap • Tie or relate background from others to PI’s previous work: • Tie the PI’s previous work to a gap statement: For some diseases, a whole organism screen may actually be necessary to break new therapeutic ground. Our work recently identified six novel classes of chemicals that cure model organisms … through mechanisms distinct from directly killing the bacterium itself. Anti-infectives with new mechanisms of action, [specifically agents that evolve from those previously identified in our laboratory,] are urgently needed to combat widespread antibiotic resistance in pathogens. Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

28. Research Strategy – SignificanceSignificance for each Specific Aim • Significance of each specific aim – includes gap statements, importance to society (significance to health), innovation, mechanistic approach that can be used for future studies Identifying novel modulators of infection by the NIH priority pathogen Microsporidia(Aim 1). Microsporidia are emerging human pathogens whose infection mechanisms are almost completely unknown. Further, they inflict agricultural damage and are on the EPA list of waterborne microbial contaminants of concern. This screen could identify not only useful chemical research probes and compounds that kill these pathogens outright, but also those that enhance host immunity. Identifying novel regulators of fat metabolism (Aim 2). Disregulation of metabolism results in many common and expensive chronic health conditions; diabetes alone affects 24 million Americans. Screening with a strain of C. elegans will likely reveal novel energy regulators of therapeutic value. Identifying novel regulators of infection by the pathogen S. aureus(Aim 3). S. aureus is life-threatening for immune-compromised patients. Recently, MRSA strains have created an urgent need for therapeutics with a new mechanism of action. We will identify genetic regulators of C. elegans host’s response to infection by S. aureus. These will lead to potential drug targets useful for boosting human immunity. Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

29. Research Strategy – SignificanceSignificance beyond Specific Aims • Not a specific aim, but a byproduct – significance and data sharing • Summarize significance in the final paragraph Creating open-source software for the C. elegans community. C. elegans is used … by more than 11,000 researchers in 750 laboratories worldwide (http://www.WormBase.orgJanuary 2010), and the close-knit community rapidly shares methods. Thus, in addition to the discovery of potential drugs and drug targets related to metabolism and infection, which could significantly impact the global burden of human disease, our aims will yield open-source software for automated, accurate, quantitative scoring for a wide range of C. elegans image-based assays that are currently intractable. The impact will be multiplied by laboratories worldwide using the resulting software to study a wide variety of pathways relevant to basic biological research and human disease. Carolina Wählby, Ph.D., (Broad Institute) National Institute of Allergy and Infectious Disease, 2011

30. Research Strategy – SignificancePreliminary Data / Progress Report • Preliminary Data: • Describe preliminary data that are relevant – Show the Data! • Tie your own data to the hypothesis – Ideally, use findings from previous work to develop new hypotheses and design studies • Important in new applications to document credibility, experience, and competence (in innovation if a novel approach) • Important in renewals to show progress and how the old project guides the hypotheses of the new project

31. Research Strategy – SignificancePreliminary Data / Progress Report • Preliminary Studies • Relate to proposed Specific Aims • Can be included in Significance, Innovation, or Approach Preliminary Studies for New Applications: For new applications, include information on Preliminary Studies. Discuss the PD/PI’s preliminary studies, data, and or experience pertinent to this application. … preliminary data can be an essential part of a research grant application and help to establish the likelihood of success of the proposed project. Early Stage Investigators should include preliminary data (however, for R01 applications, reviewers will be instructed to place less emphasis on the preliminary data in application from Early Stage Investigators than on the preliminary data in applications from more established investigators).

32. Research Strategy – SignificancePreliminary Data / Progress Report • Progress Report for Renewal and Revision Applications • Relate to previous specific aims (and new specific aims, ideally) Progress Report for Renewal and Revision Applications. For renewal/revision applications, provide a Progress Report. … Summarize the specific aims of the previous project period and the importance of the findings, and emphasize the progress made toward their achievement. Explain any significant changes to the specific aims and any new directions including changes to the specific aims and any new directions including changes resulting from significant budget reductions. A list of publications, patents, and other printed materials should be included (Progress Report Publication List).

33. Research Strategy – SignificanceHow to be successful • Hypothesis-Driven, Mechanistic Studies (not descriptive) • Old grants: descriptive / correlative • Impact of CPH on RA function – see what happens • Descriptive hypothesis: “With Disease X, RV function is impaired and RV expression of SERCA falls” • Modern grants: mechanistic / translational • Why does what we know already happens, happen? • How can we change what we know already happens? • Mechanistic hypothesis: “If we modulate SERCA expression up/down in Disease X, RV function will improve/deteriorate” • Preliminary studies can include descriptive studies, but Specific Aims should be mechanistic

34. Research Strategy – SignificanceWhy is your research important? Marc R. Moon, M.D. Joseph C. Bancroft Professor of Surgery Division of Cardiothoracic Surgery & Center for Diseases of the Thoracic Aorta Washington University School of Medicine St. Louis, Missouri AATS Grant Writing Workshop, March 2011