STUDIES OF SENSORY-MOTOR FUNCTIONS RESPONSIVE TO GRAVITY IN GENETICALLY 
ALTERED MODEL SYSTEMS

Release Date:  October 16, 2000

RFA:  DC-01-001

National Institute on Deafness and Other Communication Disorders
 http://www.nidcd.nih.gov/
National Aeronautics and Space Administration
 http://www.nasa.gov/
National Institute on Aging
 http://www.nih.gov/nia/

Letter of Intent Receipt Date:  December 18, 2000
Application Receipt Date:       January 17, 2001

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

This initiative seeks to stimulate research utilizing specific, well-
characterized transgenic and mutant animal models to elucidate molecular bases 
for the normal development and function of sensory-motor mechanisms that 
detect and respond to gravity. Gravitational loading plays an important role 
in the development (maturation and aging) of the body’s gravity-sensing 
organs, notably the vestibular receptors, the proprioceptors, the central 
motor pathways and the skeletal muscles. These functions are fundamental to an 
organism’s ability to control its balance and posture, locomotion and other 
volitional movements, and its spatial orientation. A deeper understanding of 
the interactions between gravity and mechanisms of gene expression in sensory-
motor functions would impact the fields of developmental biology, vestibular 
and motor physiology, space biology and space medicine.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas. This Request for Applications (RFA), 
“Studies of Sensory-motor Functions Responsive to Gravity in Genetically 
Altered Model Systems,” is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of 
the Federal government. Foreign institutions are not eligible, subcontracts to 
foreign organizations are allowable, with sufficient justification.  
Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.

Submission of an application in response to this RFA precludes concurrent 
submission of any other application containing substantially the same research 
proposal.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) 
Exploratory/Developmental Grant (R21) award mechanism. This mechanism is 
utilized for pilot or feasibility studies to support exploratory research that 
may lead to innovative advances in the sciences. Responsibility for the 
planning, direction, and execution of the proposed project will be solely that 
of the applicant. The total project period for an application submitted in 
response to this RFA may not exceed three years.  

This RFA is a one-time solicitation. The anticipated award date is Aug 1, 
2001. It is expected that feasibility/pilot data generated by these grants, if 
promising, will serve as a basis for a more extensive follow-up investigation, 
typically pursued through the submission of an R01 grant application. Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the customary 
peer review procedures.
 
FUNDS AVAILABLE 

The collaborating Agencies intend to commit approximately $1,000,000 Total 
Cost in Fiscal Year 2001 to fund up to six R21 grants in response to this RFA. 
An applicant may request a project period of up to three years and a budget 
for direct costs of up to $100,000 per year. These grants shall be 
administered according to NIH and grants policies and procedures. Because the 
nature and scope of the research proposed may vary, it is anticipated that the 
size of each award will also vary. Although the financial plans of the NIDCD, 
NASA and NIA provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. At this time, it is not known if this RFA 
will be reissued.

RESEARCH OBJECTIVES

Background

On June 21 and 22, 1999, the National Institute on Deafness and Other 
Communication Disorders (NIDCD) and the Life Sciences Division of the National 
Aeronautics and Space Administration (NASA) co-sponsored a program planning 
workshop, “Role of Transgenic and Knockout Studies in Understanding Sensory-
Motor Performance in Altered Gravitational Performance.” A report of this 
workshop is available on the NIDCD Web site at 
http://www.nidcd.nih.gov/news/releases/99/june99.asp. This workshop explored the viability 
of studying the effects of altered gravitational exposure on sensory-motor 
function in genetically altered experimental model systems. Specifically, the 
workshop explored two interrelated questions concerning the use of genetically 
altered model systems. Can such models contribute to advancing our 
understanding of: 1) the development and function of sensory-motor mechanisms 
that detect and respond to gravity, and 2) the effects of altered 
gravitational exposure on such sensory-motor functions? 

Recent advances in molecular genetics have greatly enhanced the search for the 
genetic determinants of complex biobehavioral functions. The generation of 
mutant and transgenic animal models, involving such species as the mouse, 
Drosophila, zebrafish and Caenorhabditis elegans (C. elegans), provides 
powerful tools for elucidation of these functions. By illustration, a large 
number of zebrafish and mouse mutants with vestibular system involvement have 
been developed. Most have phenotypes with multiple defects and variable 
penetrance and expression. Notable exceptions are the tilted and tilted head 
mouse mutants, having only one identified phenotypic defect, the absence of 
otoconia, and 100% penetrance. The genetic bases for these mutants have not 
yet been established. By contrast, targeted deletion of genes such as Math1 (a 
mouse homolog of the Drosophila proneural gene atonal) or sequences encoding 
BRN 3.1 and BDNF produces congenital sensorineural anomalies of the inner ear. 
Although the existence of additional anomalies of the nervous system or other 
organ systems is difficult to exclude, the existing animal models are a 
valuable resource for understanding molecular bases for normal inner ear 
development. 
 
The expanded use of mutant and transgenic animals offers many promising tools 
for investigating molecular bases of balance function and sensory-motor 
performance. For example, the identification of regulatory sequences of genes 
expressed specifically in the vestibular system will allow the targeted 
introduction of foreign genes into the vestibular system of transgenic mice.  
These genetically-engineered animals could be designed to create specific 
animal models of human disease. In addition, such studies could facilitate 
targeted expression of potentially therapeutic genes to the vestibular system 
epithelium.

The vestibular system is the primary sensor of angular and linear (including 
gravity) acceleration of the head. However, since all tissues in the body have 
mass, gravitoinertial acceleration also affects regional blood distribution, 
pulmonary function, movements of the abdominal viscera within the peritoneal 
cavity and both intraocular and intracranial pressure. Hence, sensory signals 
from these other organ systems also contain information about instantaneous 
linear and angular acceleration of the body. The sum of constant linear 
accelerations may be termed the gravitoinertial environment. Established 
chronic manipulations of effects of the gravitoinertial environment on 
different tissues include hypergravity, microgravity, exposure of fish embryos 
to simulated “free-fall” in a bioreactor and tail suspension/hindlimb 
unloading models in mammals. Since these manipulations affect multiple sensory 
systems, particular attention must be devoted to controls that discriminate 
vestibular from non-vestibular effects of exposure to altered gravitoinertial 
environments.

Gravitational loading plays an important role in the development of the 
gravity-sensing organs, central motor pathways and both the structure and 
function of the skeletal muscles. Since the behavior of terrestrial animals 
has evolved under the static (1G) gravitational environment of earth, both the 
direction and magnitude of gravitational acceleration may be important 
implicit variables in molecular processes related to development, maturation 
and aging of the inner ear and of sensory-motor performance. The gravitational 
load also shapes the development and maturation of the extra-vestibular (e.g., 
proprioceptive) pathways that contribute to postural control. These pathways 
may play an important role in trophic interactions between motoneurons and 
muscle fibers. Alterations of the gravitational field cause widespread effects 
in many behaviors and physiologic domains. For example, recent studies have 
shown that chronic exposure to altered gravitoinertial environments can alter 
otolith morphology and vestibulo-ocular reflex performance in developing 
zebrafish. The neuromuscular system responds to altered gravitational load 
with shifts in expression of myosin isoforms and physiologic properties of 
muscle fibers. At the molecular level, exposure to microgravity (during space 
flight) can alter mRNA expression in a variety of adult mammalian tissues. A 
deeper understanding of interactions between gravity and mechanisms of gene 
expression would benefit the fields of developmental biology, space biology 
and space medicine.

There is the need and opportunity to stimulate research utilizing specific, 
well-characterized transgenic (“knockout”/null expression, “knockin” and 
conditional expression) and mutant animal models to elucidate molecular bases 
for the normal development and function of sensory-motor mechanisms that 
detect and respond to gravity. Appropriate animal models include C. elegans, 
Drosophila, Xenopus laevis, zebrafish and the mouse, although other relevant 
models may emerge.

Scope

This purpose of this RFA is to encourage the submission of applications for 
fundamental research that address at least one of the following goals:

o  Elucidate the molecular bases for functional development of sensory-motor 
mechanisms that detect and respond to gravitoinertial acceleration in a 1G 
environment,

o  Identify the molecular bases for functional maintenance and aging of normal 
sensory-motor function in a 1G environment, 

o  Elucidate the influence of altered gravitoinertial environments on 
molecular bases for functional maintenance and aging of sensory-motor systems, 
and

o  Develop conditional knockout/knockin and transgenic models with restricted 
spatial and temporal gene activation programs that address these issues.

Example of studies that address these goals include, but are not limited to:

o  Identification of the genetic bases for morphogenesis of the vestibular 
labyrinth,

o  Identification of the molecular bases for the development and maintenance 
of functional organization of sensory epithelia, including mechanisms 
regulating hair cell generation and normal establishment of the functional 
polarity of hair cells in the neuroepithelium,

o  Identification of the molecular bases for development of the afferent and 
efferent organization of vestibular neuroepithelia,

o  Identification of the molecular bases of and the influence of gravity on 
development of the cupulae and maculae in the inner ear, including a 
clarification of the role of gravity in the formation and maintenance of 
otoconia,

o  Identification of the effects of maturation of vestibular and extra-
vestibular graviceptive pathways on trophic interactions between motoneurons 
and muscle fibers,

o  Identification of the molecular bases for development and maturation of 
sensory-motor pathways in the central nervous system that sense and respond to 
gravity, and

o  Characterization of the molecular mechanisms underlying altered performance 
of motor units and muscle fibers (e.g., atrophy and modified patterns of 
myosin expression) under altered gravitational conditions.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH solicitation, 
internet addresses (URLs) should not be used to provide information necessary 
to the review because reviewers are under no obligation to view the Internet 
sites. Reviewers are cautioned that their anonymity may be compromised when 
they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NIDCD staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be sent by December 18, 2000 to:

Dr. Daniel Sklare
Scientific Programs Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400C, MSC 7180
Bethesda, MD 20892-7180

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants. These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach. The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff. The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $100,000 per year. The total direct costs must 
be requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $100,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative (F&A) costs] for the initial budget 
period. Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested for 
each year.  This is not a Form page.

o Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000. List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of key personnel, and their 
role on the project. Indicate whether the collaborating institution is foreign 
or domestic. The total cost for a consortium/contractual arrangement is 
included in the overall requested modular direct cost amount.  Include the 
Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested (i.e., number of modules requested changes from 
one year to the next).

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual"s qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for all 
key personnel, following the instructions below. No more than three pages may 
be used for each person. A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations,

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application. Type the RFA number 
on the label. Failure to use this label could result in delayed processing of 
the application such that it may not reach the review committee in time for 
review.  In addition, the RFA title and number must be typed on line 2 of the 
face page of the application form and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Craig Jordan, Ph.D.
Chief, Scientific Review Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400C, MSC 7180
Bethesda, MD  20892-7180

Applications must be received by January 17, 2001. If an application is 
received after that date, it will be returned to the applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the NIDCD. Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NIDCD in accordance with the review criteria stated below. As part of the 
initial merit review, all applications will receive a written critique and may 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Deafness and Other Communication Disorders Advisory 
Council and the National Advisory Council on Aging.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. In the 
written comments reviewers will be asked to discuss the following aspects of 
the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals. Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application. Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score. For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) Significance: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive this 
field?

(2) Approach: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

(4) Investigator: Is the investigator appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

(5) Environment: Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements? Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children, as appropriate, for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Schedule

Letter of Intent Receipt Date:    December 18, 2000 
Application Receipt Date:         January 17, 2001
Peer Review Date:                 March 2001
Council Review:                   May 24, 2001
Earliest Anticipated Start Date:  August 1, 2001

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review),
o  availability of funds,
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Daniel A. Sklare, Ph.D.
Scientific Programs Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400C, MSC 7180
6120 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-1804
FAX:  (301) 402-6251
Email:  daniel_sklare@nih.gov

David L. Tomko, Ph.D.
Biomedical Research and Countermeasures Program
Life Sciences Division
National Aeronautics and Space Administration
Code UL, 300 E Street, SW
Washington, DC 20546-0001
Telephone:  (202) 358-2211
FAX:  (301) 358-4168
Email: dtomko@hq.nasa.gov

Judith A. Finkelstein, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue
Bethesda, MD 20892
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email: jf119k@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Sherry Dabney
Acting Chief, Grants Management Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400B, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email: sd203o@nih.gov

Mr. Lawrence P. Chambers
Research Management
Life Sciences Division
National Aeronautics and Space Administration
Code UL, 300 E Street, SW
Washington, DC 20546-0001
Telephone:  (202) 358-2196
FAX:  (301) 358-4168
Email: lchamber@hq.nasa.gov

Ms. Linda Whipp 
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda, MD 20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: lw17m@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.173 and 93.866. Awards are made under authorization of Sections 301 and 405 
of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92. This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products. In addition, Public 
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children. This is consistent with the PHS 
mission to protect and advance the physical and mental health of the American 
people. 



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