BIOLOGICAL MECHANISMS OF NOISE-INDUCED HEARING LOSS

Release Date:  May 30, 2000

RFA:  DC-00-002

National Institute on Deafness and Other Communication Disorders 
(http://www.nidcd.nih.gov/)
National Institute on Aging (http://www.nih.gov/nia/)

Letter of Intent Receipt Date:  July 15, 2000
Application Receipt Date:       September 21, 2000

THIS RFA USES “MODULAR GRANT” AND “JUST-IN-TIME” CONCEPTS.  THIS RFA INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA.

PURPOSE

The purpose of this Request for Applications (RFA) is to solicit research 
grant applications addressing the biological mechanisms of noise-induced 
hearing loss (NIHL).  The focus of this RFA is to understand the biological 
consequence of noise as a primary cause of hearing loss.  Research 
opportunities include identifying mechanisms of cellular injury and survival, 
understanding genetic factors influencing susceptibility, and identifying 
pharmacologic avenues for protection and rescue from NIHL.  The fundamental 
goal of this research is improved diagnosis, treatment and prevention of NIHL.

Although not participating in this RFA, the National Institute on 
Environmental Health Sciences has a strong interest in the environmental 
factors influencing NIHL.

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 RFA "Biological Mechanisms of 
Noise-Induced Hearing Loss" 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 and foreign, 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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) 
exploratory/development grant (R21) mechanism.  This mechanism is designed to 
support feasibility/pilot studies leading to an R01.  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 two years.  This RFA is a one-time 
solicitation.

For administrative reasons, all applications received in response to this 
solicitation will be assigned initially to the National Institute on Deafness 
and Other Communication Disorders  (NIDCD).  Following discussions among the 
participating Institutes and before review, applications will be reassigned to 
the Institute(s) or Federal Agency in DHHS that is programmatically most 
appropriate.  Because the scope of some of the research projects proposed in 
response to this RFA encompasses the interests of several NIH Institutes, 
applications may receive dual assignments based on established PHS guidelines.  
Awards will be made and managed by NIDCD and/or the other participating 
Institutes or DHHS Federal Agencies.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining procedures of the NIH.  Complete 
and detailed instructions and information on Modular Grant applications 
can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm. 

FUNDS AVAILABLE

It is anticipated that NIDCD will have approximately $750,000 total costs and 
NIA will have approximately $250,000 total costs available for this initiative 
in Fiscal Year 2001 and that up to seven (7) awards will be made.  
Applications submitted in response to this RFA must not exceed $100,000 per 
year in direct costs and the total project period may not exceed two (2) 
years.  The earliest anticipated date of award is August 1, 2001.  Although 
the financial plans of the NIDCD and NIA provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of funds for 
this purpose and the receipt of meritorious applications.

Direct costs will be awarded in modules of $25,000, less any overlap or other 
necessary administrative adjustments. Facilities and Administrative costs will 
be awarded at the negotiated rate.

RESEARCH OBJECTIVES

Background

Noise-induced hearing loss (NIHL) continues to be a major public health 
issue.  Ten million Americans have already suffered irreversible damage 
from noise, and thirty million more are exposed to dangerous levels of 
noise each day.  Although various aspects of NIHL have been under 
investigation for several decades, a comprehensive and systematic 
understanding of the biological mechanisms of NIHL remains elusive.  A 
workshop, “Research Opportunities on the Biology of Noise-Induced 
Hearing Loss” was held in Washington, D.C. on December 11 and 12, 1998 
to identify current research opportunities addressing NIHL.  Twelve 
invited scientists presented their ideas for research opportunities in 
NIHL.  Included in this RFA are a number of potential areas for 
investigation identified by workshop participants.

Scope and Objectives

Historically, issues central to the study of NIHL include subject variability 
in response to experimentally-induced hearing loss.  In addition to 
variability observed within experimental groups, incongruities between 
experimental paradigms, varying levels of noise exposure and the time frames 
selected for the assessment of NIHL damage, and the use of different animal 
models have made comparisons of studies difficult.  

Current biomedical research on the cellular, molecular and genetic factors 
contributing to human disease presents significant opportunities to advance 
our understanding of NIHL.  Limiting the variance in NIHL research may require 
the use of additional biological markers and measures, the use of cloned 
animals or the selection of an animal model with the least variance for study.  
While animal models with low variance may be especially necessary in research 
studies investigating underlying biological mechanisms, they may be less 
appropriate for a clinical model of NIHL in humans given the inherent and 
significant variance in NIHL seen from patient to patient.  Thus, several 
models may be required based on their ability to shed light on differing 
aspects of NIHL.

Both temporary threshold shift (TTS) and permanent threshold shift (PTS) are 
dynamic processes with primary and secondary effects.  Examination of the 
transitional phases between TTS and PTS in the acquisition of NIHL is required 
since measurements of these states made at fixed intervals may not be 
representative of the balance between the inherent reparative and damage 
processes of the system.  Understanding the cellular and molecular biological 
basis of TTS and PTS, identifying lesions potentially recoverable by 
pharmacological intervention, and defining when in the reparative process 
intervention should occur are important issues to be answered.  Studying gene 
expression changes as well as investigating acoustic trauma as it relates to 
the final common pathway(s) for other forms of traumatic injury or disease 
should provide insight into the basic biological mechanisms of NIHL.

This RFA solicits research applications in the following areas:

o  The study of cell injury, cell death and cell survival as related to 
NIHL.
Illustrative examples include: determining the role and site of action of 
free-radical generation and those of reactive oxygen species, e.g., the 
reactive oxygen species cascade and metabolites in NIHL; analyzing gene 
expression in NIHL as well as its relationship to aging and cell death 
pathways; assessing the dynamic changes that correspond to noise-induced cell 
injury, with focus on the impact of structural and functional changes at the 
cellular level; further defining inner ear stress defenses including heat 
shock proteins, excitotoxic antagonists, and neurotrophins; and identifying 
the role of cell death pathways, including apoptosis and necrosis activated in 
response to acoustic injury. 

o  Investigations of susceptibility to NIHL focusing on genetic or 
environmental factors.  
Illustrative examples include: identifying genetic factors leading to 
increased NIHL susceptibility or resistance in humans and in animal models; 
studying transgenic animals that exhibit NIHL predisposition or NIHL 
resistance; and identifying or correlating susceptibility to age related 
hearing loss with susceptibility to acoustic trauma.

o  Investigations focused on protection and rescue from NIHL.
Illustrative examples include: biological protection from inner ear stressors 
and the activation of inner ear stress defenses; studies of pharmacologic 
manipulations and interventions preventing/reducing NIHL; developing drug 
delivery systems for rapid intervention in NIHL; designing assays to identify 
susceptibility to NIHL; as well as identifying the cellular mechanisms of 
protective paradigms.  

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their subpopulations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  This policy results from the 
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should 
read the "NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research," which was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for 
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and is available 
on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them.  This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects” that was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and is available 
at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide additional 
relevant information concerning the policy.

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 and 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 Institute 
staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by July 15, 2000 to:

Dr. Craig Jordan
Chief, Scientific Review Branch
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 496-8683 
Fax:  (301) 402-6250
Email: jordanc@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  The form is 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. It is also available at: 
http://grants.nih.gov/grants/funding/phs398/phs398.html

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 in 
section 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 courier/overnight mail service)

At the time of submission, send TWO additional copies of the application and 
five (5) sets of appendices to:

Dr. Craig Jordan
Chief, Scientific Review Branch
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 496-8683 
Fax:  (301) 402-6250
Email: jordanc@nih.gov

Applications must be received by September 21, 2000.  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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for 
responsiveness to this RFA by the NIDCD.

Those applications that are complete and responsive to this RFA will be 
evaluated for scientific and technical merit by the appropriate review 
group convened by the NIDCD in accordance with the 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 applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the NIDCD National 
Advisory Council and/or 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.  The 
reviewers will comment on the following aspects of the application in their 
written critiques, to judge the likelihood that the proposed research will 
have a substantial impact on the pursuit of these goals.  Each of the criteria 
will be addressed and considered by reviewers in assigning an 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 a 
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:    July 15, 2000
Application Receipt Date:         September 21, 2000
Peer Review:                      January 2001
Council Review:                   May 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 strongly encouraged.  The opportunity to 
clarify any issues or answer questions from potential applicants is welcome. 

Direct inquiries regarding programmatic issues to:

Dr. Amy Donahue
Chief, Hearing and Balance/Vestibular Sciences Section
Scientific Programs Branch
National Institute on Deafness and other Communication Disorders
6120 Executive Blvd MSC 7180
Bethesda, MD  20892-7180
Telephone: (301) 402-3458
Fax: (301) 402-6251
E-Mail: amy_donahue@nih.gov

Dr. Judith Finkelstein
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone: (301) 496-9350
Fax: (301) 496-1494
Email: jf119k@nih.gov

Direct inquiries regarding fiscal issues to:

Ms. Sherry Dabney
Grants Management Officer
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400-B, MSC 7180
Bethesda, MD 20892-7180
Telephone: (301) 402-0909
Fax: (301) 402-1758
Email: Sherry_Dabney@nih.gov

Mr. Joe Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212
Bethesda, MD 20892-9205
Telephone: (301) 496-1472 
Fax: (301) 402-3672
Email: je14j@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No.93.866 (NIA), 93.173 (NIDCD). Awards are made under authorization of the 
Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by 
Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program 
is not subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review. Awards will be administered under PHS 
grants policy as stated in the NIH Grants Policy Statement (October 1, 1998).

PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the nonuse 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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