Transcript Does Retrograde Cerebral Perfusion Improve Outcome During Arch

Research Strategy – Significance
Why 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
Research Strategy – Significance
Structure of the Proposal
• Text of a grant:
– Specific Aims - Statement of the problem (introduction)
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Significance (includes background) (1-2 pages)
Innovation (½ page)
Approach – how the problem will be solved
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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
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
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
Research Strategy – Significance
Why is your research important?
• Introduction to Specific Aims:
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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)
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.
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3-4 key facts – critical problem with significance to the
society and funding agency
Research Strategy – Significance
Why is your research important?
• Introductory Paragraph:
– Show them you are competent
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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:
Research Strategy – Significance
What 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
Research Strategy – Significance
What 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.”
Research Strategy – Significance
What 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.”
Research Strategy – Significance
What makes a topic significant?
• Know your audience – review the committee roster
• AATS (http://www.aats.org)
Research Scholarship Committee
• TSFRE (http://www.tsfre.org)
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Research Committee
• NIH:
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Center for Scientific Review (http://cms.csr.nih.gov)
Office of Extramural Research (http://era.nih.gov/roster)
Research Strategy – Significance
What 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 Adult that “… 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 1year mortality of 17 to 40 percent.” These data indicate that IMR is a
common problem, but underappreciated.
Research Strategy – Significance
What 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.”
Research Strategy – Significance
What makes a topic significant?
• Make sure the organization to which you are applying considers
the organization you are quoting to be important
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.
• Funding agencies generally do not care about the goals,
objectives, or strategic plan of other funding agencies
Research Strategy – Significance
What makes a topic significant?
• FOA: Funding Opportunity Announcement
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Identify areas of increased priority and/or emphasis
May be sponsored by one or more NIH institutes.
• PA:
Program Announcements
• RFA: Requests for Applications
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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.
Research Strategy – Significance
Writing the Significance section
• Significance and Innovation
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Avoid jargon
Make it understandable to all (write science for the
clinicians, and write clinical aspects for the scientists)
• Logical, clear compelling argument
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Why the proposed study is necessary
– Highlight “Gaps” in knowledge and how your project
addresses the gaps
How it differs from previous work
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Specific ways it is innovative
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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.
Research Strategy – Significance
Writing the Significance section
• Multiple Specific Aims
– http://grants.nih.gov/grants/forms.htm
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.
• A combination of both is appropriate
Research Strategy – Significance
Writing the Significance section
• Significance section includes background:
– Summarize important results outlined by others
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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?
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Why is it essential to find out?
Research Strategy – Significance
Writing the Significance section
• Health Relevance
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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
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Research Strategy – Significance
Writing the Significance section
• Background / Significance:
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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
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Educate a reviewer who is unfamiliar with you and topic
Research Strategy – Significance
Writing the Significance section
• Start with a general significance statement (organization & expert):
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
• Follow with some background, and a gap statement:
For many diseases, researchers have identified successful novel therapeutics or
research probes by applying technical advances in automation to highthroughput 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
Research Strategy – Significance
Writing the Significance section
• Significance – Organization (NIH PA)
Enabling high throughput screening (HTS) in whole organisms is recognized as
a high priority (NIH PA-08-024).
• Authoritative expert opinion related to planned experimentation
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
Research Strategy – Significance
Writing the Significance section
• Background / Significance:
– Integrate your previous findings within the background – show
reviewers the relevance of your previous contributions
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.
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Bridge your hypotheses and long-term objectives to the
background review (and ideally your previous work)
Carolina Wählby, Ph.D., (Broad Institute)
National Institute of Allergy and Infectious Disease, 2011
Research Strategy – Significance
Background / Competence
• Previous methodology development and mechanistic investigation
– From other investigators:
Altered levels of SERCA have been found in monocrotalinetreated rats, …
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From your own laboratory:
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 …
Research Strategy – Significance
Background / Competence
–
From your co-investigators:
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).
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From your institution:
The Wash U approach, analyzing high-speed tissue-tagged MRI images in realtime, 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).
Research Strategy – Significance
Background / Competence
• Peer-reviewed validation of the importance of your line of research
– Awards and Honors:
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.
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Foundation “Starter” Grants:
The development of our unique methodologic approach was
supported by a research grant from the Thoracic Surgery
Foundation for Research and Education.
Research Strategy – Significance
Competence / Knowledge Gap
• Tie or relate background from others to PI’s previous work:
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.
• Tie the PI’s previous work to a gap statement:
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
Research Strategy – Significance
Significance 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
Research Strategy – Significance
Significance beyond Specific Aims
• Not a specific aim, but a byproduct – significance and data sharing
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.
• Summarize significance in the final paragraph
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
Research Strategy – Significance
Preliminary 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
Research Strategy – Significance
Preliminary 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).
Research Strategy – Significance
Preliminary 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).
Research Strategy – Significance
How to be successful
• Hypothesis-Driven, Mechanistic Studies (not descriptive)
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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”
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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
Research Strategy – Significance
Why 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