NOVEL THERAPEUTIC AND PATHOGENETIC STUDIES OF OCULOMOTOR DISORDERS

RELEASE DATE:  October 28, 2002

RFA:  EY-03-001

National Eye Institute (NEI)  
 (http://www.nei.nih.gov)

APPLICATION RECEIPT DATES:  March 27, 2003, and November 21, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA 

The National Eye Institute (NEI) encourages the submission of investigator-
initiated applications to develop novel therapeutic and pathogenetic 
approaches to disorders that affect ocular motility.  These disorders include 
strabismus syndromes, myasthenia gravis, congenital fibrosis syndromes, 
congenital nystagmus, and other disorders that compromise eye movement in the 
orbit and thus limit visual acuity.  Many of these disorders, such as 
strabismus, are common in childhood and can lead to permanent visual loss if 
uncorrected.  Present treatments are largely surgical in nature, with uneven 
success and the need for repeated surgery.  Therapy for symptoms such as 
pain, pressure, or double vision present in some disorders is solely 
palliative in nature.  The mechanisms of pathogenesis for these disorders is 
largely unknown.

Responses to this announcement may include applications for basic or applied, 
preclinical or clinical research.  Applications may broadly address novel 
therapeutic strategies and/or new insights into the pathogenesis of 
oculomotor diseases.

RESEARCH OBJECTIVES

Eye movement disorders represent a diverse set of diseases that have in 
common the compromised movement of the eye and related structures within the 
bony orbit.  Extraocular muscle tissue and connective tissues in the 
periphery and efferent premotor and motor pathways in the central nervous 
system that drive motor outflow are among the identified targets of this 
group of diseases.  As a group, these diseases differ significantly in 
etiology from muscular dystrophies and neurodegenerative disorders that 
affect other skeletal muscles, including Duchenne muscular dystrophy and 
amyotrophic lateral sclerosis.  Extraocular muscle are rarely affected in 
these latter diseases, and eye movement functions are selectively spared, 
even in advanced stages of the disease.  The etiology of the differential 
involvement of eye muscles and the oculomotor system in these disorders is 
unknown.  One goal of this Program Announcement is to advance our 
understanding of this differential sparing of the oculomotor system, 
particularly as it informs our understanding of oculomotor-targeted diseases.

The following examples are not intended to represent an exhaustive listing.  
They are suggestive of the diverse nature of oculomotor-selective disease and 
illustrate the need for research to identify the underlying etiologies.  
Advances in these areas will aid the development of rational therapy and 
treatment regimens.

o  Strabismus syndromes include a range of disorders that affect binocular 
fixation of the eye.  Strabismus may lead to amblyopia, which affects three 
to five per cent of the US population.  Patients present with misalignment of 
the visual axes -- deviation of one eye inward (esotropia) or outward 
(exotropia) compared to the other eye --resulting in compromised depth 
perception and binocular vision.  Strabismus may be caused by anatomic 
abnormalities of the orbits, eyes and/or extraocular muscles.  Surgical 
treatment is imperfect, with a 20 - 50% failure rate, necessitating repeat 
surgeries.  Untreated or uncorrected strabismus leads to amblyopia, the 
permanent loss of binocular vision, and low or reduced visual acuity.  
Congenital fibrosis extra ocular muscle syndromes (CFEOMs) are rare inherited 
human strabismus syndromes that also present with limited and restrictive 
globe movement.  There is evidence of extraocular muscle tissue abnormalities 
secondary to neuropathology in the oculomotor, abducens, and trochlear 
nuclei.  Several genes associated with CFEOMs have been mapped, but most are 
unidentified and their function is not understood.

o  Myasthenia gravis is an autoimmune disorder primarily targeting the 
acetylcholine receptor at the neuromuscular junction of skeletal muscle, 
leading to muscle weakness and neurodegeneration. The skeletal muscles 
involved vary; most myasthenia gravis patients have ocular muscle 
involvement.  The fluctuating weakness in the extraocular and facial muscles 
causes ocular misalignment.  The pathophysiology underlying the diverse 
phenotypes and differential involvement of extra ocular muscles is unknown.

o  Graves' ophthalmopathy (GO) is the clinical involvement of the eyes seen 
in Graves' disease, or hyperthyroidism.  GO is characterized by an increase 
in the volume of orbital tissues leading to periorbital edema, 
exophthalmoses, and extraocular muscle dysfunction.  Few treatment options 
beyond palliative care are available for the ocular pain and double vision 
that are the clinical symptoms of GO.  In severe cases, blindness may result.  
Autoimmune processes and metabolic insults targeting fibroblasts and fatty 
connective tissues within the orbit have been proposed as pathologic bases 
for this disease.

On March 7-8, 2001, the NEI hosted a workshop on Craniofacial Muscle 
Specialization and Disease, bringing together scientists and clinicians from 
the U.S. and Europe.  The group explored what is known about the unique 
characteristics of extraocular and other craniofacial muscles that render 
them selectively vulnerable or resistant to disease.  The workshop was 
timely, given recent scientific progress identifying regulatory factors for 
muscle development and new hypotheses for the role of orbital tissues in eye 
movement.  Advances in noninvasive imaging technology have also had an impact 
on craniofacial muscle research.  The goal of the workshop was to 
characterize the common features of three unique muscle types -- extraocular, 
laryngeal, and mandibular -- to build a framework for future research 
directions.  Workshop participants discussed the structure, function, 
development and biochemistry of these craniofacial muscle classes and the 
diseases that are craniofacial muscle-selective or craniofacial muscle-
resistant.  Analyzing the biology and disease phenotypes across these three 
muscle types is essential to the identification of pathogenetic mechanisms 
that distinguish craniofacial disease from other skeletal muscle disorders.

The workshop concluded with a discussion of research needs in the area of 
craniofacial muscle biology and disease.  The recommendations stressed the 
importance of collaborative research across multiple disciplines to promote 
new insights into the pathogenesis of craniofacial-selective and 
craniofacial-resistant diseases.

Summary and Scope

The manifestations of disorders of the oculomotor system can be readily and 
reliably identified in the clinical setting; however, the pathogenesis, 
therapy, and treatment of these disorders remain problematic.  This RFA 
invites investigators with diverse scientific interests to apply their 
expertise in basic and applied laboratory and clinical research to enhance 
our understanding of normal and pathologic ocular motility.  Examples of 
research topics that are considered responsive to this RFA are listed below.  
This list is not meant to be an exhaustive, exclusive, or delimiting set of 
topic areas:

o  Function:  Delineation of the functional anatomy of the oculomotor system, 
including the cellular and molecular organization underlying the 
biomechanical properties of extraocular muscle during development and in 
normal and pathological aging of the oculomotor system.

o  Pathogenetics:  Identification of the cellular and molecular targets of 
oculomotor disease and disease pathogenesis; the differential cellular and 
molecular organization of extraocular and classical skeletal muscle that is 
informative in oculomotor system-targeted diseases; the role of the immune 
system and hormone factors; and candidate disease genes for rare inherited 
oculomotor disorders.

o  Development/Regeneration:  Understanding the development of the 
extraocular and related craniofacial muscles and central neural pathways that 
make them selectively vulnerable or resistant to disease and distinct from 
that of other skeletal muscle, including the identification of transcription 
factors, growth factors and apoptotic processes.  Explore the use of gene 
transfer therapies to strengthen extraocular muscle tissue.  Utilize stem 
cells and tissue engineering to produce myogenic and neuronal precursors for 
restoration of function.

o  Research Resources:  Develop research resources to aid in the 
identification and treatment of ocular motility disorders.  These could 
include animal models, imaging techniques for improved diagnosis and 
monitoring of oculomotor disease, ocular kinematical models, newer chemical 
and molecular markers, new and novel therapeutic surgical approaches.


MECHANISM OF SUPPORT

This RFA will use NIH R01 award mechanism.  As an applicant you will be 
solely responsible for planning, directing, and executing the proposed 
project.  This RFA has two solicitation dates.  Future unsolicited, 
competing-continuation applications based on this project will compete with 
all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures.  The anticipated award dates are December 
1, 2003, and July 1, 2004.

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.

FUNDS AVAILABLE

The NEI intends to commit approximately $2 Million in FY2003 and in FY2004 to 
fund ten to twelve new and/or competitive continuation grants in response to 
this RFA. An applicant may request a project period of up to five years.  
Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary.  Although the financial plans of the NEI 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.

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.

SPECIAL REQUIREMENTS

Applications which propose to develop research resources to aid in the 
identification and treatment of ocular motility disorders should propose a 
plan to make these resources available to the vision research community.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Staff Contact Name

Chyren Hunter, Ph.D.
Division of Extramural Research
National Eye Institute
Building EPS, Room 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  301-402-0528
Email:  [email protected]

o Direct your questions about peer review issues to:

Samuel C. Rawlings, Ph.D.
Chief, Scientific Review Branch
Division of Extramural Research
National Eye Institute
Building EPS, Room 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  301-402-0528
Email:  [email protected]

o Direct your questions about financial or grants management matters to:

William W. Darby
Grants Management Officer
National Eye Institute
Building EPS, Room 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  301-496-9997
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: [email protected].

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: 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, one additional copy of the application must be 
sent to:

Samuel C. Rawlings, Ph.D.
Chief, Scientific Review Branch
Division of Extramural Research
National Eye Institute
Building EPS, Room 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  301-402-0528
Email:  [email protected]

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  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.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NEI.  Incomplete applications will be returned to the 
applicant without further consideration.  And, if the application is not 
responsive to the RFA, CSR staff may contact the applicant to determine 
whether to return the application to the applicant or submit it for review in 
competition with unsolicited applications at the next appropriate NIH review 
cycle.

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 NEI in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a process in which applications will be discussed and assigned a 
priority score
o Receive a second level review by the National Advisory Eye Council.

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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 
tactics?

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

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

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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.

o INCLUSION:  The adequacy of plans to include subjects from both genders, 
all racial and ethnic groups (and subgroups), and children as appropriate for 
the scientific goals of the research.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
included in the section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data.

o BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

o OTHER REVIEW CRITERIA:

The adequacy of the proposed plan to share research resources.

RECEIPT AND REVIEW SCHEDULE

Application Receipt Date:  March 27, 2003, and November 21, 2003
Peer Review Date:  May/June, 2003, and February/March, 2004.
Council Review:  October, 2003, and May, 2004
Earliest Anticipated Start Date:  December 1, 2003, and July 1, 2004.

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.

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete 
copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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.

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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:  The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

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.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 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.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.867, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  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 described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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