OCULAR ALBINISM (OA1) AND RETINAL GANGLION CELL DEVELOPMENT

RELEASE DATE:  January 14, 2003

RFA: EY-03-003

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

APPLICATION RECEIPT DATE:  August 15, 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 Where to Send Inquiries
o Letter of Intent
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) wishes to promote research on the 
pathogenesis and treatment of Ocular Albinism 1 (OA1) and related 
developmental disorders.  Individuals with OA1 demonstrate a congenital 
reduction or absence of melanin pigment in the eye, which results in poor 
visual acuity.  Recent research on the enzymes and genes involved in the 
production of melanin has provided a deeper understanding of the molecular 
genetic defects associated with albinism.  The pathology of OA1 also includes 
developmental disturbances in retinal ganglion cell (RGC) axon development.  
These lead to visual abnormalities such as nystagmus, strabismus, foveal 
hypoplasia, photophobia, and refractive errors.

This Request for Applications (RFA) solicits basic, translational, and 
clinical research projects which will provide a clearer understanding of OA1 
as well developmental retinal disorders affecting the number and routing of 
central visual projections.  Knowledge gained by research in this area will 
provide the scientific rationale for new forms of diagnosis and treatment.

RESEARCH OBJECTIVES

Background

Albinism refers to a heterogeneous group of congenital disorders in melanin 
pigment biogenesis.  These conditions are characterized by a reduction or 
total absence of pigment in the hair, skin, and eyes.  Ocular albinism is a 
subgroup of disorders arising from a reduction of melanin pigment in the 
retinal pigment epithelium (RPE).  Pigment deficits in the RPE also lead to a 
reduction in the number and distribution of photoreceptors and other retinal 
cells by affecting the mechanisms controlling cell proliferation during the 
early development of the retina.  Such hypo-pigmentation of the RPE is 
associated with the misrouting of RGC axons at the optic chiasm.  This 
results in abnormal projections to visual centers in the thalamus and cortex.

OA1 is the most common form of ocular albinism.  It is an inherited, X-linked 
disorder wherein the RPE lacks pigment while the skin and hair are normal.  
The pathology of OA1 includes disturbances in the factors which affect the 
number of retinal cells and their proliferation during early retinal 
development.  These errors in RGC axon development and guidance lead to 
developmental abnormalities such as myopia.  A less frequently occurring form 
of ocular albinism, oculocutaneous albinism or OCA, is a group of congenital, 
mostly autosomal recessive but occasionally autosomal dominant disorders.  
OCA is characterized by a generalized disruption in melanin pigment synthesis 
in the hair, skin, and eyes.  OCA and OA1 give rise to a similar 
constellation of visual disorders.

A number of developmental disorders related to OA1 affect formation of the 
optic nerve.  These include the Angelman, Apert, Ch diak-Higashi, Griscelli, 
Hermansky-Pudlak, Optic Nerve Hypoplasia (ONH), Prader-Willi, Septo-optic 
Dysplasia (SOD), and Waardenburg syndromes.  The pathogenesis of these 
conditions includes factors affecting the number of retinal cells and their 
proliferation during early retinal development.  ONH and SOD are not 
associated with defects in melanin metabolism.

Research Objectives and Scope

The goal of this RFA is to stimulate and support research that can provide a 
clearer understanding of developmental retinal disorders, misrouting of optic 
nerve axons, and abnormalities of the optic nerve related to the pigment 
deficits found in ocular albinism and similar developmental disorders.  Such 
research may require interdisciplinary studies including neuroscientists, 
cell biologists and clinicians.  Studies using human tissue, appropriate 
animal models, and clinical subjects are encouraged.  However, clinical 
trials and broad population-based studies will not be supported by this 
initiative.

Suggested research topics may include, but are not limited to:

o  Development of new treatments for OA1 and related diseases.

o  Determination of the role of pigmentation deficits on the development of 
the retina, including neurogenesis, differentiation, and distribution of 
retinal cells.

o  Identification of the influence of tyrosinase expression and melanin 
production on RPE and RGC fate.

o  Study of the development and distribution of retinal cells.

o  Study of the genetics of albinism as it relates to the visual system and 
misrouting of retinal ganglion cell axons to their central targets.

o  Elucidation of the relationship between hypo-pigmentation and refractive 
errors.

o  Determination of how pigment deficits in the in the RPE lead to 
abnormalities of axonal guidance in the developing visual system.

o  Determination of the developmental mechanisms associated with OHN and SOD 
which lead to reduced numbers of RGC axons and related abnormalities of the 
optic nerve.

o  Determination of the function of the OA1 gene product.

o  Development of a clearer understanding of the genetic mechanisms necessary 
for the normal biogenesis of RPE melanosomes in visual tissues.

o  Development of new diagnostic tests for OA1.

o  Determination of the mechanisms which disrupt retinal foveal development 
in OA1 and related disorders.

MECHANISM OF SUPPORT

This RFA will use the NIH R01 award mechanism.  As an applicant you will be 
solely responsible for planning, directing, and executing the proposed 
project.  This RFA is a one-time solicitation.  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 date is April 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 $1.5 million in FY 2004 to fund 
approximately two to four new and/or competitive continuation grants in 
response to this RFA.  An applicant may request a project period of up to 
five years and a budget for direct costs commensurate with the proposed work.  
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 provides 
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.

ELIGIBLE INSTITUTIONS

You may submit an application 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.

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:

Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda MD  20892-7164
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  pad@nei.nih.gov

o  Direct your questions about peer review issues to:

Samuel C. Rawlings, Ph.D.
Chief, Scientific Review Branch
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda MD  20892-7164
Telephone:  (301) 496-5561
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
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda MD  20892-7164
Telephone:  (301) 496-5884
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 
http://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.

o  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.

o  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.

o  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, two additional copies of the application must be 
sent to:

Samuel C. Rawlings, Ph.D.
Chief, Scientific Review Branch
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda MD  20892-7164
Telephone:  (301) 496-5561
FAX:  (301) 402-0528
Email:  rawlings@nei.nih.gov

o  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 (IC).  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?

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

(1)  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.

(2)  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)

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

RECEIPT AND REVIEW SCHEDULE

Application Receipt Date:  August 15, 2003
Peer Review Date:  October, 2003
Council Review:  January, 2004
Earliest Anticipated Start Date: April 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

o  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 Office of Management and Budget (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.

o  INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy that children (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).

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.

o  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.

o  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.

o  PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:  The 
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.

o  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.

o  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.

o  AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.387, 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 PHS 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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