Download The Art and Science of Research Grant Writing

The Art and Science of
Research Grant Writing
What makes a good grant?
Lots of things....
1. Good grants:
- are creative
- fill gaps in our knowledge about a topic
- tell a good story
2. Relevant to the goals of the funding agency (Not
really that important here, but something to keep in
mind)
3. Good grants are able to convince your peers to fund
you
- Must be well-written, clear, easy to read
- Answers the “so what?” question
Reasons Reviewers Reject
Proposals
http://www.niaid.nih.gov/ncn/grants/write/write_d6.htm
•Problem not important enough.
•Study not likely to produce useful information.
•Studies based on a shaky hypothesis or data.
•Alternative hypotheses not considered.
•Methods unsuited to the objective.
•Problem more complex than investigator appears to realize.
•Etc.
•Etc.
•Etc.
• As the proposal is being assembled and drafted, look over these points
on the website and ask yourself if any of them apply to your grant.
• Grant reviews are partially subjective because everyone is biased toward
certain techniques, experimental approaches and models.
Getting Started...
What is your hypothesis?
What biological question are you trying to address?
What are your objectives?
Are they clear?
What are your main experimental approaches?
Are they the most appropriate to meet your objectives?
Grant Sections
• Body
• Budget
– budget justification
• Supplementary information and other
forms.
http://grants1.nih.gov/grants/funding/phs398/phs398.html#forms
Body of the Proposal
The questions that NIH wants addressed:
What do you intend to do?
Why is the work important?
What has already been done?
How are you going to do the work?
Specific parts:
ABSTRACT (very important)
a. Specific Aims
b. Background and Significance
c. Preliminary Studies/Progress Report
d. Research Design and Methods
Additional Sources
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http://nextwave.sciencemag.org/cgi/content/full/2001/09/27/1#top
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http://grants.nih.gov/grants/grant_tips.htm
•
http://www.niaid.nih.gov/ncn/grants/default_research.htm
HOW TO WRITE YOUR FIRST GRANT
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Nothing beats a good idea
Be realistic
Make the presentation clear and simple
Make the presentation easy to read
Present yourself as the greatest expert in
the field - You need to make yourself
FIRST in whatever category you choose
• Submit a realistic budget
SIX STEPS TO DEVELOP A
COMPELLING NOVEL IDEA
1. Define the problem you want to address (what is your
niche)
2. Collect and critically analyze background information
related to problem
3. Develop a preliminary idea (don’t force it)
4. Assess the idea’s potential for success and modify it, if
necessay
5. Seek constructive criticism from knowledgeable
colleagues
6. Refine the idea to maximize its potential for impact on
your field
NOTHING BEATS A GOOD IDEA
• Articulate a worthwhile, single, focused
objective
• Articulate Specific Aims that are clearly related
to one another and logically fit under the
umbrella of the overall objective
• Present gaps in our knowledge (Thoroughly
search the literature)
• Plant the seed for achieving each specific aim
by presenting the questions to be asked which
will fill the gaps
BE REALISTIC
• Ask questions which are answerable
• Provide tantalizing preliminary data as
evidence that the questions are worth
asking and answerable
• Propose technical approaches which are
within the realm of your published
technical expertise OR provide preliminary
data
• The volume of work proposed should be
proportional to the time of support
requested and your other obligations
MAKE THE PRESENTATION CLEAR AND
SIMPLE
• Assume total ignorance on the part of the
reviewer (make application reviewer friendly)
• Provide all of the simplest conceptual
background
• No abbreviations or acronyms without
definition
• Use diagrams and cartoons to illustrate
concepts
• Use formatting for emphasis
• Be redundant
MAKE THE PRESENTATION EASY TO READ
• Think of the reviewer – You must Sell your
idea
• Avoid verbosity
• Adopt a unique style of presentation
• Tell the reviewer what he is supposed to
think and write
• Do not force the reviewer to hunt through
the application for information
PRESENT YOURSELF AS THE GREATEST
EXPERT IN THE FIELD
• Know the literature in depth and breadth
• Do not make statements without attribution
or preliminary data
• Do not be reluctant to admit shortcomings
• Seek collaborators or mentors when your
expertise cannot be documented
• KEY POINT: The key to success in grant
writing is to engender enthusiasm in the
reviewer – who then becomes an
advocate for the proposal
SUBMIT A REALISTIC BUDGET
• Request only what you need and you can
defend
• Justify every item in the budget thoroughly
• Do not request less than you need
• Present evidence that your institution
supports your research
THE RESEARCH PLAN
• Very important: this is what reviewers read
before they accept the reviewing
assignment
• State briefly your hypothesis, significance,
specific aims, expectations and impact
THE RESEARCH PLAN
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Specific Aims
Background and Significance
Preliminary Studies
Research Design and Methods
Human Subjects
Vertebrate Animals
Literature Cited
Consortium/Contractual Arrangements
Consultants
SPECIFIC AIMS
• One short paragraph to identify system
• One short paragraph to describe
regulatory steps of the system
• One short paragraph containing a one
sentence CENTRAL HYPOTHESIS
• One short sentence stating each aim
individually
• Follow each with a simple statement
describing what you will do to satisfy that
aim
Example: Research Plan
Specific Aims
Prolactin (PRL) is one of the most versatile hormones of mammalian organisms.
Besides its role in lactation, secretion of PRL contributes to a wide range of
physiological functions, i.e. adaptation to new environment (22), immune functions
(23) osmoregulation (24,25), reproduction (26) and behavior (27). PRL of anterior
pituitary origin is secreted by lactotrophs (28). Lactotrophs have spontaneously high
secretory activity, which is controlled primarily by tonic inhibitory input of
hypothalamic origin (29), though they receive stimulatory input, as well (29-31).
The physiological PRL inhibiting factor is dopamine (DA) (32,33). DA is released from
three, anatomically and functionally distinct hypothalamic neuroendocrine cell
populations: I). periventricular hypothalamic dopaminergic (PHDA) neurons of the
periventricular nucleus (A14), II) tuberohypophysial (THDA) and III)
tuberoinfundibular (TIDA) neurons (34) of the arcuate nucleus (A12). PHDA and
THDA neurons terminate in the intermediate and neural lobes of the pituitary gland,
respectively (35,36). DA, released from THDA/PHDA terminals may reach the
anterior lobe through the short portal vessels. On the other hand, TIDA neurons
terminate in the external zone of the median eminence supplying the anterior
pituitary gland with DA through the long portal vessels. Although the central role of
TIDA neurons in hypothalamic control of PRL secretion is acknowledged, the relative
contribution and importance of the distinct neuroendocrine DAergic neuron
subpopulations to the regulation of PRL secretion is not understood.
Studies from our (37-39) and other (40-43) laboratories suggest
that the daily activities of all three DAergic neuroendocrine
neuron populations exhibit similar rhythmic changes (i.e. high in
the morning, low in the afternoon). Although, the amplitudes of
these rhythms of TIDA, THDA and PHDA populations are
differentially modulated by ovarian steroids, the presence of
rhythms is independent of the ovarian steroid background in
female rats in all neuroendocrine DAergic neuron populations.
Our CENTRAL HYPOTHESIS is that the rhythmic activity in
all three populations of neuroendocrine DAergic neurons
are paced by direct circadian input from the
suprachiasmatic nucleus while its amplitude is modulated
by interneuron-mediated input, ovarian steroid
background, and PRL feedback from the pituitary gland. In
this application, we will focus on the role of direct
suprachiasmatic input, PRL feedback and signaling
mechanisms in the generation of rhythmic patterns of DA
release from the TIDA, THDA and PHDA by pursuing the
following SPECIFIC AIMS:
To characterize the chronobiological and anatomical basis of regulatory
mechanisms governing the rhythmic patterns of the DAergic input on PRL
secretion. By conducting in vivo experiments in constant environments we will
test whether the daily changes in the activities of neuroendocrine DAergic neuron
populations are light entrained endogenous circadian rhythms. Tract tracing
studies will be used to investigate the functional anatomical nature of the direct
connection(s) between the circadian zeitgeber in the suprachiasmatic nucleus
and the different neuroendocrine DAergic subpopulations. Antisense antagonism
will be used to verify the functional significance of suprachiasmatic efferent fibers
on the neuroendocrine DAergic neuron populations.
To characterize the feedback role of PRL in the daily activity of PHDA, THDA
and TIDA neurons. The incidence of PRL-Rs in the THDA and TIDA neurons is
higher than in PHDA neurons, although PHDA neurons also express PRL-R in
ovarian steroid-replaced rats. We suggest that PRL feedback is inherently part of
the THDA and TIDA neurons’ circadian regulation and it is inducible in PHDA
neurons by ovarian steroids. In order to verify this hypothesis, we will compare
the effects of PRL on the activity of PHDA, THDA and TIDA neuron populations in
ovariectomized and ovarian steroid-replaced rats.
To identify the signal transduction mechanisms involved in the circadian
regulation of the secretory activity of hypothalamic neuroendocrine
DAergic neurons. We will identify the receptors, second messenger and cellular
effector systems involved in mediating the effects of circadian input and PRL
feedback on the neurosecretory activity of the PHDA, THDA and TIDA neuron
subpopulations.
BACKGROUND AND SIGNIFICANCE
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Provide just enough background
information so the reviewer appreciates
what you are proposing
Extraneous information is distracting
Compartmentalize information with bold
headings, key words and sentences
Make copious use of diagrams and
cartoons
Use a terminal sentence pointing to your
goal at the end of each compartment
The neuroendocrine DAergic neuron populations and their feedback regulation
(Fig. 1)
The hypothalamic A14 and A12 cell groups (Fig. 1), which are exclusively comprised
of DAergic neurons (64,65) provide the pituitary gland with DA through two different
routes: I) The tuberoinfundibular DAergic (TIDA) neurons send short projections to
the external zone (EZ) of the median eminence. TIDA axons terminate on the
basement membrane of the perivascular space surrounding the primary capillary
loops of the portal system. From here the long portal vessels (LP) carry DA of TIDA
origin to the anterior lobe (AL) of the pituitary gland. Perikarya of TIDA neurons show
bimodal rostrocaudal distribution (66). The majority of TIDA neurons originate
throughout the arcuate nucleus (ARN, A12), and a smaller
Fig. 1
population arises from the periventricular nucleus (PeVN, A14) (66). II) The
tuberohypophysial DAergic (THDA) neurons of the rostral ARN (A12) and the
periventricular hypothalamic (PHDA) neurons of the PeVN (A14) have long axons,
which course through the pituitary stalk (PS) and terminate in the neural (NL) and
intermediate (IL) lobes of the pituitary gland, respectively (35). Short portal
vessels (SP) provide communication between the neurointermediate and the AL
(Figure 1).
The terminal areas of the TIDA, THDA and PHDA axons are neurohemal
zones, which lack the blood-brain barrier. The absence of the blood-brain
barrier and the continuity between the pericapillary space and the liquor
space are the anatomical bases for a free, most likely bi-directional
communication between axon terminals and the blood-liquor space (67).
While all three neuroendocrine neuron populations express PRL-Rs in
female rats, the incidence of PRL-Rs on THDA and TIDA neurons is higher
than in PHDA neurons (21). Changes in the ovarian steroid background
and/or serum PRL levels differentially affect the abundance of PRL-R in the
neuroendocrine DAergic neuron populations (21). Although to different
extents, the activities of TIDA (68,69), THDA and PHDA neurons are indeed
affected by PRL in the peripheral blood (DeMaria, Lerant and Freeman,
1999, submitted). Of these neuroendocrine DAergic neuron populations, the
autoregulatory properties of the PHDA neurons seem to most closely
resemble the well-characterized nigrostriatal dopaminergic neurons as both
nigrostriatal DAergic (70,71) and PHDA neurons (72) seem to be inhibited
by D2/3–type DA (auto)receptors. There are data, however, indicating that
TIDA neurons can be influenced by both D1 and D2 receptors, but the
responses are different from that seen in nigrostriatal DAergic neurons (73).
D2 receptor agonists were reported to stimulate TIDA neurons (74), while
specific D1 agonists inhibit the reserpine- or neurotensin-evoked TIDA
activation (75). We provide preliminary data demonstrating that D2 receptors
do not colocalize with TIDA neuron terminals in the median eminence. This
suggests that D2/3 receptors do not act as presynaptic autoreceptors on
TIDA neurons. We will test our hypothesis that PRL provides the primary
feedback in the THDA and TIDA neurons instead of D2/3 autoreceptors.
SIGNIFICANCE
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Be imaginative
Avoid unrealistic ideas
Keep it simple (KISS rule)
Be brief
Present in layman’s terms if possible
PRELIMINARY EXPERIMENTS
• Present preliminary data which supports
the feasibility of each specific aim
• Do not present preliminary data which will
completely accomplish the specific aim
• Present preliminary data which proves you
can use a new technique
• Present preliminary data to support your
development and validation of a previously
undescribed technique
RESEARCH DESIGN AND METHODS
GENERAL METHODS
• Present most often used methods first
each in separate titled paragraphs
• Present in a depth which is inversely
proportional to your published experience
with the methods
• Cite publications in which you have used
the methods
• Refer to the preliminary data when
describing unpublished methods
Example: Preparation of tissue for immunocytochemistry (ICC)
Rats are sacrificed by an overdose of sodium pentobarbital, and
perfused through a transcardial cannula with 50 ml of ice cold
phosphate buffer (PBS, 0.1 M, pH 7.34, 295 mosm) immediately
followed by 100 ml of ice cold fixative. The fixative applied usually is
4 % paraformaldehyde (PFA, in 0.1 M PBS, pH 7.5). The brains and
pituitaries are postfixed for an hour in situ. After removal the brains
and pituitaries are rinsed in PBS and immersed in 20% sucrose
solution (in PBS, at 4ºC) until sinking. The tissue blocks are frozen
on the freezing stage of a HM500OM cryostat (Zeiss, Germany).
The brains are cut in 35-m coronal section between 300-4200 m
post bregma and collected into 4 parallel series of free-floating
sections. The sections are stored in cryoprotectant solution (133)
until ICC is initiated. If the aforementioned tissue block does not
contain an area with established immunoreactivity for the antigen in
question, other areas of the brain (or other organs) are processed to
provide positive and negative controls for the immunostaining. The
pituitary glands are cut in 10-20 m coronal or horizontal sections,
thaw-mounted on gelatin-subbed glass microscope slides and
stored at -80ºC in closed tissue boxes containing Dryerite. Both the
free floating brain sections and the mounted pituitary sections are
thoroughly washed (5 X in PBS) prior to ICC. We have had ample
experience with these techniques (21,37,38)
RESEARCH DESIGN AND METHODS
Experimental approaches to each Specific
Aim
• Each specific aim is its own section
• State specific aim
• State hypothesis associated with that
specific aim
• State question(s) associated with that
hypothesis
• Provide rationale for each question
• Describe experiments
• Expected results, interpretation,
shortcomings and pitfalls
OUTLINE OF A TYPICAL SPECIFIC AIM
• Specific Aim I
Hypothesis A
Basis of hypothesis A
Question 1
Rationale for question
Experiment 1, 2, 3, 4……….
Question 2
Rationale for question
Experiment 1, 2, 3, 4……….
Experimental results, interpretation,
shortcomings, pitfalls
Hypothesis B………….
HYPOTHESIS
• Each Specific Aim should be
HYPOTHESIS DRIVEN
May consist of more than one
hypothesis
• Hypothesis should be defended in terms of
the overall objectives previously stated
Do not be afraid of redundancy with
the Background
EXPERIMENTAL QUESTIONS
• Each question should logically fit under the
umbrella of its hypothesis
• The rationale for each question should
serve to clarify the question, the necessity
for asking the question and its relationship
to the hypothesis
What is to be gained by asking this
question?
EXPERIMENTS
• Describe each experiment in sufficient
detail so the reviewer can understand it
and believe you can successfully complete
it
Do NOT forget controls
Do NOT forget statistical analyses
Explain rationale for doses and times
Refer to previously described general
methods
Describe methods unique to this
experiment
EXPECTED RESULTS AND INTERPRETATION
• State ALL expected and unexpected results
• State the interpretation of each
What will you do if one of the
unanticipated results emerge?
Be very careful that an unanticipated result
does not doom the subsequent specific
aims/questions
SHORTCOMINGS, PITFALLS, LIMITATIONS
• What are possible alternative approaches?
Why are you using the approach you
are?
Why are you not using one of the
alternatives?
What are the strengths and
weaknesses of the approach you are using?
• Are there any pitfalls you foresee?
How will you deal with them?
• What are your lab’s strengths and
weaknesses?
HUMAN SUBJECTS/VERTEBRATE ANIMALS
• Follow the instructions carefully
• Verbosity with detail is good
• Be realistic about number of
subjects/animals
• Be aware of rules governing limitations of
use
SUMMARY STATEMENT
• I assist the reviewer by writing my own
summary statement as if I were the reviewer
Significance, Approach, Innovation,
Investigator, Environment
• Be brutally honest
Strengths, Weaknesses and Shortcomings
• What will the project accomplish?
• What will the project not accomplish?
CONSULTANTS/COLLABORATORS
• Use consultants for techniques that you intend to
use for the first time
Secure letters confirming their role
• Interest collaborators in supplying unique
reagents that are critical to your work
Antibodies, nucleotides, peptides
Obtain letters of collaboration
• Have a senior level colleague with the greatest
experience obtaining grants and serving on
Study Sections read and critique the application
YOU CAN CONTROL THE FATE OF THE
APPLICATION BEFORE MAILING
• Review the charge and membership of the
possible Study Sections to which it may be
assigned
http://www.csr.nih.gov/committees/rosterindex.asp#A
• Write a cover letter to be included in your
application package
Request assignment to the Study Section
you select
COMMON REASONS GRANT
APPLICATIONS RECEIVE UNFUNDABLE
SCORES
• Poor organization
Not an integrated body of work
• Exercise in data collection
“Fishing expedition”
• Work too descriptive and not experimental
“OK, so you showed that there is message for
the insulin receptor on the pancreas, now what?”
COMMON REASONS GRANT
APPLICATIONS RECEIVE UNFUNDABLE
SCORES
• Lack of sufficient detail
• Insufficient convincing preliminary data
• Applicant not capable of performing the
work
• Inadequate institutional support
• Objective not very important to health and
disease
• Overly ambitious
WHAT DO I DO IF APPLICATION IS NOT
APPROVED FOR GRANT FUNDING?
• Find out why
Ask SRA and Institute official
Obtain Summary Statement
Read Summary Statement thoroughly and
often
Ask a mentor to read Summary Statement
Mentor and yourself should highlight
issues for attention
WHAT DO I DO IF APPLICATION IS NOT
APPROVED FOR GRANT FUNDING?
• Re-write application
• Respond to Summary Statement by:
Enumerating each criticism and the
actions you propose to take
WHAT ACTIONS SHOULD I TAKE?
• Take the criticism constructively
No finger pointing or accusations
Admit the reviewers were right
• Articulate your response to each
Reorganize and simplify presentation
Provide more detail
Provide preliminary data in response
Get a consultant
Add experiments
Eliminate experiments
DIPLOMATICALLY point out reviewer error
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This is a revision of our previous application reviewed by the
Biochemical Endocrinology (BCE) Study Section in October
1998. We have taken the reviewers’ critiques constructively
and made the requested changes, which we believe,
improved the current application. We thank the reviewers for
providing insight into the shortcomings of our proposal. We
have addressed each criticism below and have made
appropriate changes in the text as indicated in Century
Schoolbook font.
Response to Critique 1:
Criticism: The second question posed in Specific Aim I
does not relate the changes in neuronal activity
associated with the rhythm of water intake to the
pharmacology of the DA receptor under investigation and
no discussion of the effects of dehydration on food
intake and other variables is presented.
Response: In agreement with the reviewer, we have
eliminated the water deprivation experiments from this
proposal.
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Criticism: The rationale for use of unilateral
versus bilateral injection sites of
[biotinylated dextran] tracer is not apparent
nor is the choice of a seven day waiting
period following tracer injection justified.
Response: To answer the question of
anatomical projection, unilateral injections will
provide sufficient information. Also, it is easier
to interpret the results of unilateral injections,
since we cannot exclude the possibility of SCN
efferents crossing the midline. The seven day
survival period gives excellent results with the
BDA-F tracer as shown by several laboratories
(1-3). We now include these explanations and
citations at the proposed experiments as well.
AND NOW………….
• You can do nothing more…….
SO……
AWAIT THE AWARD
NOTICE!!!!!!!
A final piece of advice...
Do not wait until
the week prior to
the due date to
write your grant
proposal!
Acknowledgements
Some slides were provide by:
Marc E. Freeman, Ph.D., Department of Biological Science,
Florida State University, Tallahassee, FL
And
Winston Thompson, PhD, Morehouse School of Medicine,
Atlanta, GA