NIH Goals

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NIH Goals

• The goals of NIH-supported research are to
• advance the understanding of biological systems,
• improve the control of disease, and enhance
  health.
• New Roadmap Initiative Emphasizes initiatives
  that will dramatically change the content or
  process of medical research. Elias Zerhouni,
  Director NIH, Science 30263-74, 2003.
• Remember It is the National Institute of Health
  not the National Institute of Mechanisms

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Reviewer Instructions from NIH

• Significance a) Study addresses an important
  problem, b) How will aims advance knowledge, c)
  Impact of study on concepts or methods in field.
• Approach a) Conceptual framework, design,
  methods, analyses are developed and appropriate,
  b) Potential problems and alternative approaches
  are acknowledged.
• Innovation a) Novel concepts, approaches or
  methods, b) Aims original and innovative, c)
  Challenge existing paradigms or develop new
  methods or techniques.
• Investigator a) PI is trained and productive, b)
  Collaborators provide appropriate expertise
  needed, c) Publications together.
• Environment a) Environment contribute to
  success, b) Proposed experiments take advantage
  of unique features of environment and/or useful
  collaborations, c) Evidence of institutional
  support.

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What Reviewers Read

• Two critical sections are the Abstract and the
  Specific Aims Section. The Reviewers read these
  first and form their opinions.
• Abstract Addresses overall long term objectives,
  specific aims or hypotheses, health relatedness.
  Describe methods and techniques. Add importance
  of data statement.
• Specific Aims a) Conceptual framework, model to
  be used b) Hypotheses to be tested (no more than
  four), c) Specific Aims that will test the stated
  hypotheses in a logical manner, d) novelty and
  potential impact of project

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What Reviewers Would Like to Read

• Abstract

• Outcomes of cortical stroke are usually
  devastating, are poorly understood and severely
  affect quality of life. The proposed project uses
  a mammalian model of focal cortical ischemia to
  examine the role of substance excitement (sub E)
  in improved recovery of function. The central
  hypothesis of this project is that sub E is a
  critical factor in improved recovery after
  cortical ischemia and that it serves as a key
  factor in inhibition of the inflammatory pathway.
  Although increased subE is known to reduce pain
  in peripheral neuropathy and other inflammation
  models by altering the prostaglandin pathways,
  its role in stroke is unexplored. We begin to
  test the role of sub E by testing three
  hypotheses
• Hypothesis 1. A general statement that you wish
  to test. Sub E is important in recovery of
  function after focal cortical lesions.
• Hypothesis 2. The mechanism of SubE mediated
  recovery after focal brain injury is through the
  inflammatory cascade by inhibition of
  prostaglandin synthesis.
• Hypothesis 3. Another broad statement, perhaps
  more mechanistic still.
• Techniques include behavioral analyses,
  behavioral pharmacology, immunocytochemistry,
  Western blot analyses, RIAs, ELISAs and imaging
  quantification. It is the long-range goal of this
  group to provide insights that will aid in
  developing novel therapeutic interventions for
  the treatment of stroke to improve functional
  recovery.

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What Reviewers Would Like to Read

• Specific Aims

• a. SPECIFIC AIMS
• The majority of patients with traumatic spinal
  cord injury (SCI) report moderate to severe
  chronic pain sensations (Bonica, 1991) that can
  be divided into spontaneous pain and altered
  sensations to peripheral stimuli or evoked pain.
  Unfortunately, these pain syndromes have remained
  refractory to clinical treatment using
  conventional analgesics such as morphine and
  related compounds. We have recently characterized
  a mammalian model of chronic central pain after
  SCI that is reproducible and demonstrates the
  development of mechanical and thermal allodynia
  (Christensen et al., 1996, appendix). This model
  of central chronic pain will allow an
  investigation of mechanisms and possible novel
  therapeutic interventions. We will focus on the
  evoked pain component as this component is well
  characterized in our model. In addition, we will
  also investigate spontaneous pain, which is not
  as well studied but clinically significant. We
  will examine the effects of two endogenous
  inhibitory transmitters systems that offer
  efficacious treatment options the serotonergic
  and GABAergic systems (SPECIFIC AIM 1).. The
  present project will use a spinal cord
  hemisection (T13) injury that results in
  mechanical and thermal allodynia. Changes in
  motor function following hemisection will be
  scored using the Basso, Beattie and Bresnahan
  (BBB) open field test (Basso et al., 1995) to
  ensure that a motor impairment does not
  compromise the nociceptive tests. Past experience
  with this model has demonstrated the development
  of behavior consistent with mechanical and
  thermal allodynia by 24 days (see Christensen,
  et. al., appendix). Consequently, we will begin
  testing the drug interventions at 30 days
  postsurgery.
• HYPOTHESIS 1 Activation of endogenous inhibitory
  transmitter systems will ameliorate the chronic
  pain behavior that develops after spinal cord
  injury.
• SPECIFIC AIM 1 To determine if serotonergic and
  GABA receptor agonists will reduce the evoked
  somatosensory behavior after spinal cord
  hemisection in a dose dependent manner.
  Experiment 1 5-HT1A and 5-HT3 serotonergic
  receptor agonists and GABAA and GABAB receptor
  agonists will each be administered intrathecally,
  30 days after spinal hemisection, at different
  doses in an effort to reverse the allodynia in
  response to mechanical and thermal stimuli. The
  drugs to be used will include 8-OH-DPAT (5-HT1A
  agonist), 1-phenylbiguanide (5-HT3 agonist),
  muscimol (GABAA agonist) and baclofen (GABAB
  agonist). Vehicle injections will be used as
  controls. Outcome measures will be evoked
  somatosensory, locomotor and spontaneous
  behavioral assays.
• SPECIFIC AIM 2 To determine if serotonergic and
  GABA transporter inhibitors will reduce the
  evoked somatosensory behavior after spinal cord
  hemisection in a dose dependent manner.
  Experiment 2 5-HT transport inhibitor
  (fluoxetine, 6-nitroquipazine) or GABA
  transporter inhibitor (guavacine, SKF

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Tips for Writing Specific Aims Section

• Must be strong, solid hypotheses and
  straightforward means of testing the hypotheses.
• Provide rationale for hypotheses to be tested.
  Justify the selection of the ones chosen in the
  context of current scientific literature.
• An outstanding hypothesis addresses an important
  biological process, disease, treatments and
  increases the understanding in that area.
• The proposal should not be driven by advances in
  technology. Avoid fishing expeditions ex. DNA
  microarray analyses or proteomics with no
  evidence of feasibility and no data.
• Write the abstract from exact statements made in
  Specific Aims section.
• Spend the most time in developing the specific
  aims page (1 ½ pages to 2 pages maximum).
• Add a simple line drawing to clarify the overall
  proposal.
• DO submit the specific aims page to experienced
  NIH grantees for presubmission critiques.

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What Reviewers Read

• The next MOST critical section is Preliminary
  Studies.
• Must present data to support hypotheses.
• Must demonstrate that proposed experiments are
  feasible by PI and collaborators.
• Explain how results are valid and how early
  studies will be expanded.
• Interpret results critically and offer
  alternative interpretations and ways to test.
• Preliminary data may be previously published by
  PI, unpublished data and publications from others.

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What Reviewers Would Like to Read

• Preliminary Studies

• c. Preliminary Studies. The following pilot data
  have been collected in our laboratory to support
  the following hypotheses
• Data to support (or test) Hypothesis 1. Restate
  hypothesis
• Experiment 1 To test for xxx, we performed focal
  cortical injuries using the model of X and
  Z.Describe what you did, n per group,
  statistical treatment, this is where you can
  showcase how rigorous and careful you are as a
  scientist. Most reviewers begin with the specific
  aims page and decide if they are enthusiastic
  about the project (which is true for about 90 of
  the submissions) and then skip to the preliminary
  studies section to determine if the investigator
  has the technical skills to do what she/he
  described. If you demonstrate feasibility of
  techniques for all your hypotheses, you will be
  in good shape. Some high risk, high impact
  techniques can be added at the very end but be
  certain to ensure success at that juncture by
  letters of collaborations of investigators who
  can do that technique.
• Figures 1 and 2 (above) demonstrate statistically
  significant attenuation of xxx (figure 1) and xxx
  (figure 2) after focal cortical lesion. Elaborate
  more here..

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What Reviewers Read

• The next MOST critical section is Research Design
  and Methods.
• Most Investigators spend the most time writing
  the Introduction but in fact, this is the least
  critical section.

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What Reviewers Would Like to Read

• Research Design and Methods

• d. Research Design and Methods
• Our overall goal is to test if and how control
  of the expression of Sub E contributes to
  improved recovery of function after focal
  cortical ischemia and to begin to understand the
  mechanisms that underlie the improved recovery.
  The general experimental design will be to use a
  naïve control group (n10), a sham control group
  (n10), a focal lesion group (n10) and a focal
  lesion group with treatment (n10). The numbers
  that we have selected have been obtained using
  power analyses and data from experiment XX above.
  These numbers are needed to determine the
  statistical significance to an alpha level
  0.001 (here find a statistician to determine
  numbers, include her/his letter of support).
  Another method is to have a section on statistics
  for each section or for the whole grant at the
  end of this Design section.
• SPECIFIC AIM 1. Restate specific aim 1.
• Experiment 1.1. Restate but elaborate here.
• Rationale
• Experimental Protocol Groups that will be
  compared,
• Predicted Results Most grants have pilot data
  collected so that the predicted results are
  already known. Remember, if the data is not
  published it is not real so it becomes eligible
  for pilot data.
• Potential Problems Here is the place to suggest
  alternative approaches.
• Significance Sentence or two on the import of
  the data produced by this experiment.
• Statistical Treatment Describe statistical
  methods. Include Power Analysis to demonstrate
  feasilbility of approach. If you have pilot data,
  you can do a Power Analysis.
• Experiment 1.2. Test whether xxxx
• Details in Methods

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Common Mistakes in Writing Grants

• Ideas not original or significant.
• Unrealistic amount of work proposed
  (overambitious).
• Project too diffuse, lacks focus.
• Rationale to do project not clear or valid.
• Project is fishing expedition and/or lacks
  hypothesis driven research.
• Studies are based on a shaky hypothesis or shaky
  data.
• Proposed experiments are descriptive and do not
  test a hypothesis.
• The proposal is technology driven not hypothesis
  driven.

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Common Mistakes in Writing Grants

• Rationale for experiments not given.
• Direction or sense of priority not clearly
  defined.
• Lack of alternative methodological approaches in
  case primary approach does not work out.
• Insufficient methodological detail to support
  feasibility (no recognition of potential
  problems).
• If initial experiment fails, the subsequent
  experiments fail.
• Proposed model system does not address the
  proposed question.
• Experiments lack relevant controls.
• Proposal innovative but lacks preliminary data.

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Common Mistakes in Writing Grants

• PI has no experience with proposed techniques and
  no collaborator who does.
• Preliminary data does not support feasibility of
  the project or hypotheses.
• Proposal lacks critical literature references so
  that reviewers think the PI does not know
  literature or purposely neglected critical
  publications.
• Not clear which data were obtained by PI and
  which data were obtained by others.
• PI has not been productive, no recognition in the
  field for which the proposal is submitted.

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Revising for Resubmission to NIH

• Discuss the summary statement and reviewers
  comments with an experienced NIH grantee who can
  help interpret what the reviewers really meant.
• Address all of the reviewers comments in your
  revision.
• Be polite. No PI has ever received funding by
  pointing out that the reviewers were wrong or
  missed something in the original application.
• Put ALL ego aside. If in doubt, do it their way.
• If reviewers recommend elimination of critical
  experiments, either explain the rationale to keep
  them or cut them. My recommendation is never
  argue with the reviewers. Revise according to the
  recommendations, get the funding and do the
  experiments anyway.
• NOTE Very few grants are funded after first
  time submission. Consequently, you will be
  revising. Our study section is funding at the
  12.5 percentile. Obviously, 87.5 of the
  proposals are not funded, including Nobel
  Laureates, Howard
• Hughes and Javitts Award recipients.

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Practical Tips for Addressing Reviewers Concerns

• Call the Program Director before submission to
  determine program relevance of your planned
  proposal.
• Call the Executive Secretary after the review
  when you receive you priority scores. The notes
  that are taken during the discussion may not
  match the written critiques submitted prior to
  the study section meeting.
• Look up NIH awards. There may be one tailored for
  you.
• Read the instructions. Do not assume the
  reviewers will have expertise in your field.
  Define all abbreviations, be clear, etc.
• BECOME A REVIEWER. Call up an Executive
  Secretary, introduce yourself on the phone and
  offer to review grants in your area of expertise
  as an Ad Hoc reviewer. This experience will
  change how you write grants.

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Summary

• Writing scientifically sound proposals is a
  challenge.
• As in experiments, there are certain formulae to
  ensure that the reviewers will understand your
  proposal.
• Call the Program Director and Executive
  Secretaries for presubmission and post-review
  information.
• Put yourself in the reviewers shoes. What would
  you like to read, late at night?
• Finally, thank you for your attention and GOOD
  LUCK !!!
• Claire E. Hulsebosch, Ph.D.
• Vice Chair and Professor
• Neuroscience and Cell Biology