OCULAR ALBINISM AND THE NEUROSCIENCE OF RETINAL GANGLION CELL AXON GUIDANCE

RELEASE DATE:  January 14, 2002

RFA:  RFA-EY-02-001

PARTICIPATING INSTITUTES AND CENTERS (ICs):

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

APPLICATION RECEIPT DATE:  May 15, 2002

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 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

Ocular Albinism Type 1 (OA1) is an inherited, X-linked disorder wherein 
skin and eye color are normal, but the retina lacks pigment.  
Individuals with OA1 show quite poor visual acuity and other visual 
abnormalities.  The pathology of OA1 includes disturbances in retinal 
ganglion cell (RGC) axon development and guidance, and other 
developmental abnormalities such as myopia.  Thus the National Eye 
Institute (NEI) wishes to stimulate and support research to increase 
our understanding of RGC axon development and guidance.  In order to 
function normally, visual system neurons must make precise connections 
during embryonic development.  Knowledge of these mechanisms is 
expected to have important links to the pathogenesis of OA1 albinism.

Suggested research topics include, but are not limited to studies of:  
RGC axon misrouting at the midline of the optic chiasm, mechanisms of 
axon target selection and determinants of pathfinding errors in the 
brain, pathogenetic links between hypopigmentation and myopia, 
melanosome biogenesis in the retinal pigment epithelium (RPE), retinal 
cell trafficking of tyrosinase, or the genetics of albinism syndromes.  
Collaborations among investigators from the neuroscience, cell biology, 
genetics, and clinical vision research communities are strongly 
encouraged in order to apply basic neuroscience approaches to 
understanding the human disease.

RESEARCH OBJECTIVES

Background

Albinism includes a group of genetic disorders that share a reduction 
in retinal melanin pigmentation and significant visual abnormalities.  
OA1 is the most common form of ocular albinism, patients suffer from 
nystagmus, strabismus, foveal hypoplasia, photophobia, refractive 
errors, and decreased visual acuity, which can compromise vocational 
choice and quality of life.  The less frequently occurring 
oculocutaneous albinism (OCA) is a heterogeneous group of congenital, 
mostly autosomal recessive but occasionally autosomal dominant 
disorders.  These include the Angelman, Chediak-Higashi, Hermansky-
Pudlak, Prader-Willi, and Waardenburg syndromes.  OCA is characterized 
by a generalized disruption in melanin pigment synthesis in the hair, 
skin, irides, and eyeground.  OCA and OA1 have similar visual outcomes.

The ocular manifestations of both OA1 and OCA include misrouting of RGC 
axons from the retina to the brain.  Axons normally develop and grow 
along pathways by extending along adjacent axons, and/or by detecting 
developmental cues.  Various cues having chemoattractive or 
chemorepellent roles have been observed in the developing visual 
system, where they control axon guidance and fiber crossing at the 
midline.  A fundamental question in the development of the visual 
system is how individual axons respond to these specific cues.  
Therefore, the abnormal axon routing seen in albinism presents an 
intriguing model system for developmental studies, particularly since 
the retinal disorganization is often associated with eye movement 
disorders and the development of myopia.

The relationship between misplaced axon projections and pigment 
deficits is a vexing and unresolved issue.  The human OA1 gene product 
appears to be a 60kD melanosomal protein.  Point mutations in 
tyrosinase, the primary enzyme of melanogenesis, lead to both the 
absence of pigment in the RPE and the appearance of visual system axons 
which cross at the optic chiasm, rather than remaining in the normal, 
uncrossed position.  It is not clear what role pigment or its absence 
plays in these phenomena, or how pigment levels in the RPE affect the 
fate of RGCs on the opposite face of the retina.

Objectives and Scope

This RFA will support studies of the basic mechanisms controlling axon 
guidance in the visual system, and other visual phenomena related to 
the albino model.  Such research may require interdisciplinary studies 
including collaborations between neuroscientists and cell biologists or 
basic scientists and clinicians.  Studies of human tissue, genetic 
material, or subjects (including patients with OA and OCA) are 
encouraged, but clinical trials will not be supported under this 
initiative.

Possible studies include, but are not limited to, the following:

o  Identify the sites and mechanisms of action of axon guidance 
molecules in order to understand how topographic gradients are 
generated.

o  Determine how factors from the melanin pigment pathway influence 
neurogenesis and RGC phenotype.

o  Determine the function of the OA1 gene product.

o  Identify signals required for sorting tyrosinase and other melanin-
associated proteins and factors to appropriate intracellular 
compartments.

o  Understand the mechanism of action of genes responsible for the 
normal biogenesis of RPE melanosomes.

o  Determine the role of OA1 in foveal development.

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 September 30, 2002.

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 $3.0 million in FY 2002 to fund 
approximately four to seven 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.  At this time, it 
is not known if this RFA will be reissued.

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:  [email protected]

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:  [email protected]

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:  [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].

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, one additional copy 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:  [email protected]

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:         May 15, 2002
Peer Review Date:                 August, 2002
Council Review:                   September, 2002
Earliest Anticipated Start Date:  September 30, 2002

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 in the Description on page 2 of the application.  
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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