Specific Aims

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• Specific Aims

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What are the 3 keys to a successful grant
application?

• Idea
• Commitment
• Grantsmanship skills

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4 IMPORTANT STEPS IN GRANT WRITING

• 1) Read the instructions
• 2) READ THE INSTRUCTIONS
• 3) READ THE INSTRUCTIONS

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• 4) ..AND THEN REALLY, REALLY READ THE
  INSTRUCTIONS.
• Read all of the instructions
• Read the current instructions
• Read RFA and PA especially well these supplied
  to reviewers
• Never Exceed Page Limits

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CHARACTERISTICS OF A GOOD GRANT WRITER

• Makes a good first impression
• Is well-prepared
• Is credible
• Delivers a clear message
• Provides supporting documentation
• Has appropriate endorsements
• Has something special to offer
• Is persistent
• Plans (lead time and quality time)
• Is clever and logical
• Perspires
• Can read.the instructions, and does
• Knows buttons and pushes them

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TIPS HOW TO SET YOUR GRANT APART FROM REST

• Write grant as though for a newspaper

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CHARACTERISTICS OF NEWSPAPER ARTICLE

• Concise
• Visually appealing
• Easy to read
• Comprehensible to wide audience
• Headline
• Effective use of illustrations/figures

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NOT RECOMMEDED

• In terms of incubation time and dose, and cell
  density, to conduct such experiments, we will
  depend on results from prior experiments
  described in Section B.2xxii, and cell
  stimulation as summarized in Section D.2xiv
  (integral to aim 3.3), to assess conditions most
  likely, both with and without inclusion of drug
  X, to yield the most biologically meaningful and
  physically distinct differences.

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KEY ISSUES

• Use simple, declarative sentences for clarity
• Avoid jargon, complicated words, endless
  abbreviations and tortuous syntax
• Consider help from an editor if English is not
  your first language
• Avoid use of weak words that convey lack of
  confidence

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WEAK WORDS

• Avoid words that may introduce doubt in the mind
  of your reviewer about your ability to do the
  work. BE ASSERTIVE.
• Example
• We will try to establish
• versus
• We expect to establish

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WEAK WORDS

• Example
• If we can demonstrate that
• versus
• We expect to demonstrate that

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WEAK WORDS

• Example
• We believe that we can
• versus
• It is our conviction that we can
• versus
• We will

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EDITORIAL SUPPORT

• Colleagues
• From graduate students in appropriate departments
• From editing services
• Enter medical editors into search engine
• Copy editing rewriting and reorganizing to
  improve clarity (35/hr)

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STRUCTURE OFIDEAL GRANT APPLICATION
IDEA
SUPPORTING IDEAS, CONCEPTS
DETAILS OF THE PLAN
APPENDICES
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STRUCTURE OFIDEAL GRANT APPLICATION

• Like a newspaper article, put the most important
  material up front
• Use new paragraphs to emphasize concepts and
  specific points and carry flow of logic
• Use later pages to provide details

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OVERVIEW OF AIMS/GOALS

• NIH Specific Aims sections
• NSF First part of Project Description
• USDA First part of Introduction Rationale
  Significance section

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SPECIFIC AIMS

• Because it is the template or master plan for the
  rest of the proposal, one of two most important
  sections in the grant application
• Short applications are simply an expanded version
  of this section
• This section works very well as a pre-proposal
• It is the most difficult section to write
• It must quickly engender enthusiasm for your idea
• The flow and logic must be linear and compelling.

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SPECIFIC AIMS

• Linear progression essential for a strong aims
  section
• Linkage, achieved by outlining, is the key to a
  bullet-proof specific aims section (4 paragraphs)
• Introductory paragraph
• What, why and whom paragraph
• Aims paragraph
• Payoff paragraph

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SPECIFIC AIMS

• Introductory paragraph
• Opening sentence is the grabber, wake-up or
  go for the heart
• Begins the flow of logic necessary to convert the
  reviewer to an advocate for your grant
• Should open with whats important to the mission
  of the funding agency
• Unknowns highlight gap in knowledge base bring
  reviewer to edge of field
• Conclude with why gap is an important problem
  that is impeding progress in field

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SPECIFIC AIMS

• So, your introductory paragraph should include
• Grabber
• Knowns
• Unknowns
• Frame problem

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SPECIFIC AIMS

• What, why and whom paragraph
• Long-range goals
• Objective of this application
• Central hypothesis and how formulated
• Rationale
• Indication that you are well-prepared

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SPECIFIC AIMS

• Long-range goal
• This is not the goal of the current application
• This is the goal of the laboratory program (of
  which the current application is a part)
• Be realistic, do not overstate or over anticipate
  your capabilities

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SPECIFIC AIMS

• Objective of this application
• Must be a logical step toward the attainment of
  the long-term goal
• Defines the purpose of the proposed research
• Must be phrased in such a way that the central
  hypothesis clearly grows out of it

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SPECIFIC AIMS

• Central hypothesis
• Make certain that you write a real hypothesis
• A tentative assumption made in order to draw out
  and test its logical or empirical consequences
• Websters
• Most grant applications must be hypothesis-driven

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SPECIFIC AIMS

• Central hypothesis
• Best bet from among alternatives
• Implicit in any hypothesis is that it could be
  invalid (thats why you are testing it)
• You must have an alternative strategy, should the
  hypothesis be invalid (you win either way)
• Testing of the central hypothesis/alternatives
  must attain the proposals objective

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SPECIFIC AIMS

• Central hypothesis do-s and donts
• Correct The central hypothesis is that
  components of automobile exhaust accelerate
  degradation of statuary in Washington, D.C.
• Incorrect The central hypothesis is to show that
  components of automobile exhaust accelerate
  degradation of statuary in Washington, D.C.
• This is the difference between a hypothesis and a
  predetermined conclusion.

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SPECIFIC AIMS

• How to link components
• Long-range goalbroadest
• Projects continuum of research for lab
• Objectivemore narrow
• Step along continuum
• What is to be achieved, regardless of how
  hypothesis tests
• Central hypothesismost narrow
• Best bet, but could be invalid (alternative
  presented later)

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SPECIFIC AIMS

• Linkage example
• Long-range goal is to reduce birth defects among
  children of farmers
• Objective of this proposal is to determine the
  cause of environmentally linked cleft palate
  syndrome
• The central hypothesis is that herbicide X is the
  causative agent (pesticide Y will be presented
  later as an alternative)

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SPECIFIC AIMS

• Rationale
• Ensure that you formulate a true rationale
• the underlying reason basis
• What will become possible that is not possible
  now
• The rationale must directly relate to the problem
  you have delineated

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SPECIFIC AIMS

• Well-prepared
• Why are investigators most qualified
• Not routine biographical information
• Summary of collective reasons why you and your
  colleagues have the competitive advantage, e.g.
• Unique qualifications of research team
• Quality and quantity of preliminary data
• Unique reagents, technologies, etc.
• Research environment

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SPECIFIC AIMS

• Environment
• Not routine equipment and resources only those
  that contribute to evaluation of merit
• Key collaborative arrangements and other unique
  features that enhance probability of success
• Extraordinary institutional commitment
• Intellectual environment conducive to successful
  completion of your research

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SPECIFIC AIMS

• Aims paragraph contains your specific aims

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SPECIFIC AIMS

• Two to four at most
• Brief, focused and limited in scope
• Each must have eye catching headline
• Conceptual, not descriptive
• Each must flow logically to next
• Must collectively test central hypothesis (be
  concordant), but have working hypothesis on their
  own
• None should be absolutely dependent on the
  outcome of others

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SPECIFIC AIMS Keep simple/direct

• Determine genotypic allele frequencies of the AAA
  and BBB genes in a closed unselected
  avermectin/milbemycin-naïve helminth population
• Determine genotypic frequencies of the AAA and
  BBB genes in a population of helminths that have
  been highly selected by frequent long-term
  treatment with AM drugs
• Identify candidate resistance alleles

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SPECIFIC AIMS

• Example of when hypothesis and specific aims are
  not concordant
• Hypothesis Compound X is genotoxic when
  activated by peroxidases.
• Rationale Due to the high levels of
  prostaglandin H synthase in breast tumors,
  peroxidase activity may be a critical factor in
  compound X-induced tumorigenesis
• Specific aims
• Characterize the genotoxic activities of compound
  X and a metabolite, compound Y, in bacterial
  mutagenesis assay
• Characterize the effects of compound X
  metabolites on DNA
• Determine genotoxic effects of compound X in
  human mammary epithelial cells

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SPECIFIC AIMS

• Payoff paragraph
• Innovation
• Expectations
• Impact

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SPECIFIC AIMS

• Payoff paragraph
• Key section in developing advocacy
• Statement regarding innovation must grow out of
  your specific aims
• Expectations must be specific and credible this
  is the return on reviewers (taxpayers)
  investment in you
• Each must be followed by a statement as to why
  that outcome is important
• Collective impact how these outcomes will
  advance your field must be summarized

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SPECIFIC AIMS

• Linear progression though aims section

GAP
OBJECTIVE
CENTRAL HYPOTHESIS
SPECIFIC AIMS
EXPECTED OUTCOMES
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What are four paragraphs for specific aims
section?

• Introductory
• What, why and whom
• Specific Aims
• Payoff

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INTRODUCTORY
Glaucoma is the leading cause of irreversible
blindness worldwide and the second most common
cause of blindness in developed countries.1,2 The
most common form, primary open-angle glaucoma, is
often associated with elevated intraocular
pressure (IOP), which develops as a result of
increased resistance to aqueous humor outflow
through the conventional drainage pathway.3-5
Clinical trials have established that IOP
reduction in open-angle glaucoma helps preserve
vision.6-9 Thus, glaucoma patients, whether
having elevated IOP or not, are managed
clinically with the objective of lowering IOP.
Initial treatments utilize pharmaceutical agents
that lower IOP by targeting aqueous secretion
and/or uveoscleral outflow functions not
directly responsible for elevated IOP in
glaucoma.10-12 This is partly because the
molecular and cellular mechanisms responsible for
reducing conventional outflow facility, thereby
elevating IOP, are currently unknown. Lacking
this knowledge is a significant obstacle because
understanding the molecular mechanisms that
underlie the regulation of outflow in the
conventional drainage pathway will facilitate the
development of more appropriate and effective
therapies for people with glaucoma.
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What, Why and Whom
Our long-range goal is to identify novel targets
in the human conventional drainage pathway for
the treatment of ocular hypertension, and hence
glaucoma. The objective of the present proposal,
as the next step towards attaining this goal, is
to examine how homotypic binding of cadherin-5
may contribute to generating outflow resistance
in the conventional drainage pathway. Our central
hypothesis is that cadherin-5 junctions between
human Schlemms canal (SC) endothelial cells
significantly influence resistance to
conventional outflow. We have formed this
hypothesis based upon (i) published data
demonstrating the involvement of
calcium-sensitive structures in conventional
outflow resistance13,14 (ii) published data from
our laboratory locating cadherin-5 between cells
of SCs inner wall15, a structure thought to
contribute to conventional outflow resistance16
and (iii) published data showing the pivotal role
of cadherin-5 in vascular endothelial
permeability/barrier function. 17-22
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What, Why and Whom (cont.)
The rationale that underlies the proposed
research is that understanding the contribution
of SC endothelial cells to total outflow
resistance, and specifically the role of
cadherin-5 binding between SC endothelial cells,
will enable the identification of novel ways to
modulate outflow resistance and consequently to
control IOP in people with glaucoma. We are
particularly well prepared to undertake the
proposed study because our research team includes
uniquely qualified individuals with combined
experience in molecular and cellular biology,
glaucoma, cadherin junction biology, biomechanics
and anterior segment ocular perfusion. Our team
members are leaders in their respective research
areas, and have the technical expertise and a
history of productive scientific interactions
needed to successfully complete the proposed
work.
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Specific Aims
We plan to test our central hypothesis and
accomplish the overall objective of this proposal
by pursuing the following three specific
aims Specific Aim 1 Assess the extent to which
adherens junctions between Schlemms canal
endothelial cells influence total outflow
resistance in the human conventional outflow
pathway. Working hypothesis Homotypic,
extracellular interactions and cytoplasmic
associations of cadherin-5 in human Schlemms
canal endothelial cells mediate resistance to
aqueous humor outflow. Specific Aim 2 Evaluate
the effect of mechanical forces on adherens
proteins in human Schlemms canal endothelial
cells. Working hypothesis Mechanical forces on
human Schlemms canal endothelial cells regulate
expression, distribution and/or phosphorylation
of cadherin-5/catenins, and hence outflow
resistance. Specific Aim 3 Evaluate the role of
Edg (endothelial differentiation gene) receptor
signaling in Schlemms canal endothelial
cell-cell adhesion and outflow facility. Working
hypothesis Regulation of resistance to outflow
at the level of adhesion between human Schlemms
canal endothelial cells occurs in part via
activation of Edg receptors.
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Payoff
Our approach, designed to better understand the
mechanisms that underpin the generation and
regulation of resistance to drainage of aqueous
humor in the conventional pathway, is innovative
for three reasons (i) we have the ability (via
specific molecular tools) to regulate protein
expression solely in human Schlemms canal
endothelial cells (ii) we can study cadherin
function in three complementary model systems
that have been validated and optimized (iii) we
will for the first time examine the dynamic
relationship between cadherin function, Edg
receptor activation, and mechanical force
application, and determine how they interact to
influence to conventional outflow function. As
outcomes of this line of research, we expect to
first demonstrate the specific contribution of
cadherin-5 and associated proteins to the
generation of total outflow resistance. Second,
we plan to determine the dynamic relationship
between outflow facility and cadherin function.
Last, we expect to show the ability to modulate
outflow facility by modulating cadherin function.
Results obtained from these investigations will
provide a fundamental understanding of the role
of cadherin proteins in aqueous outflow
resistance and uncover novel therapeutic targets
for glaucoma therapy.
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