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
https://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: clh@nei.nih.gov
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: rawlings@nei.nih.gov
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: wwd@nei.nih.gov
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
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
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
https://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
https://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:
https://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: rawlings@nei.nih.gov
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: https://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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete
copy of the updated Guidelines are available at
https://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
https://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
https://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 https://grants.nih.gov/grants/stem_cells.htm and at
https://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
https://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
https://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.