RESEARCH STUDIES ON THE HEREDITARY CALCIUM OXALATE STONE DISEASES

Release Date:  April 27, 2000

PA NUMBER: PA-00-091

National Institute of Diabetes and Digestive and Kidney Diseases

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

Urinary tract stone disease constitutes a major health care burden for the 
United States population.  Calcium oxalate is the major constituent of these 
urinary tract stones.  Studies suggest that a subset of persons who have 
chronic, recurrent urinary tract stone disease have a familial predisposition 
to the disease.  The etiology and the genetic abnormality in these persons 
are not known.  However, there is a group of individuals with known inherited 
disorders who develop recurrent calcium oxalate stones at a very early age.  
These persons have a genetic metabolic disorder known as primary 
hyperoxaluria in which a genetic defect causes excessive excretion of oxalate 
in the urine.  These primary hyperoxaluria disorders have been shown to be 
due to a defect in the regulation of oxalate synthesis in the liver, 
resulting in an accumulation of excess oxalate.  The purpose of this Program 
Announcement is to increase investigator interest in research into the 
genetics and heritability of oxalate regulation and the oxalate stone 
diseases.  The Division of Kidney and Urologic and Hematologic Diseases of 
the NIDDK has set aside specific funds for pilot and feasibility studies 
which utilize new and innovative approaches to the study of these disorders.   

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.  Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
nonprofit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) pilot and 
feasibility project grant (R21) award mechanism.  Responsibility for the 
planning, direction, and execution of the proposed project will be solely 
that of the applicant.  The total project period for an application submitted 
in response to this PA may not exceed two years.  The total amount of direct 
costs to be requested for each of the two years may not exceed $100,000 per 
year. 

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

DURATION OF PROGRAM ANNOUNCEMENT

This PA will remain active for two years, until October 2002, at which time 
applications may no longer be submitted in response to this program 
announcement.

RESEARCH OBJECTIVES

Although calcium oxalate stone disease is a very common health problem in the 
United States, there is very little new, innovative research being applied to 
the understanding of the etiology, risk factors, or genetic basis of this 
chronic disease. This announcement focuses on the heritable oxalate stone 
disorders in an attempt to better understand the metabolic and genetic 
defects responsible for the disease and to eventually develop more effective 
treatment and preventive strategies.  The calcium oxalate stone disease that 
is most commonly identified in adults is poorly understood from a basic 
science point of view. It is known that this disease tends to occur within 
families but pedigrees have not been well established or studied.  

A rare, heritable cause of nephrolithiasis has been identified and 
characterized.  This disorder results in the onset of oxalate stone disease 
early in childhood and can frequently lead to renal failure.  This disease 
(primary hyperoxaluria) is due to a defect in the liver peroxisomes of the 
enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the 
transamination of glyoxylate to glycine. The non-catalized glyoxylate is 
oxidized to oxalate and is excreted in excess in the urine.  

To address these issues and others related to calcium oxalate stone disease, 
the following are some areas in which it is suggested that applications be 
submitted:

o develop strategies to replace the gene defect in oxalosis and 
hyperoxaluria;

o develop strategies for development of new animal models for the study of 
the calcium oxalate stone diseases;

o develop strategies to assemble and investigate family pedigrees with 
calcium oxalate stone disease for risk factors, genetic defects, and other 
related factors.

Research applications need not be limited to those areas listed above.  All 
innovative proposals related to the subject are encouraged. 

Summary

It is anticipated that, as a result of the grants funded with this PA, new 
and innovative approaches will have been developed addressing the genetics 
and heritability of oxalate regulation and the oxalate stone diseases, and 
that the data obtained from these pilot studies will be effectively utilized 
by the investigators to submit competitive investigator-initiated R01 
research grant applications.  

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).
 
All investigators proposing research involving human subjects should read the 
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical 
Research," which have been published in the Federal Register of March 28, 
1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 
23, No. 11, March 18, 1994, available on the web at 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

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

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

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) and will be accepted at the standard application deadlines as indicated 
in the application kit.  Application kits are available at most institutional 
offices of sponsored research, or may be obtained from the Division of 
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-
435-0714, email: GrantsInfo@nih.gov.

Competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types are not relevant 
applications for submission under the guidelines of this PA.

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award.  It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers, 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 
below.

Budget Instructions

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $100,000 per year. The total direct costs 
must be requested in accordance with the program guidelines and the 
modifications made to the standard PHS 398 application instructions described 
below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $100,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.)  At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form page.

o Under Personnel, list key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is foreign or domestic.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.  Indirect costs for 
subcontracts are included in the total cost budget for the R21 applications 
submitted in response to this PA. The subcontract costs should not be in 
modular format but should be rounded to the nearest $1000. 

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person. A sample biographical sketch may be viewed 
at: http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST:  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.  The program announcement title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.

Submit the signed, original, single-sided application, including the 
Checklist, along with five signed photocopies and five collated sets of 
appendix materials 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)

The Center for Scientific Review (CSR) will not accept any application in 
response to this PA 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, however, amended applications either investigator initiated 
or previously submitted in response to the PA may be submitted in response to 
this RFA, but must meet the guidelines delineated in this announcement. 

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health 
Service referral guidelines.  Applications will be evaluated for scientific 
and technical merit by an appropriate scientific review group convened in 
accordance with the standard NIH peer review procedures.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of applications under review, will 
be discussed, assigned a priority score, and receive a second-level review by 
the appropriate national advisory council or board.

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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

o Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

o Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

o Innovation:  Does the project employ novel concepts, approaches, or 
methods?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies? 

o Investigator:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

o Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  Adequacy of plans to include both genders, minorities and their subgroups, 
and children as appropriate for the scientific goals of the research.  Plans 
for the recruitment and retention of subjects will also be evaluated.  The 
reasonableness of the proposed budget and duration to the proposed research 
will also be reviewed..

o  The adequacy of the proposed protection of humans, animals, or the 
environment, to the extent that they may be adversely affected by the project 
proposed in the application.

o  Availability of special opportunities for furthering research programs 
through the use of unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in the United 
States or which provide augmentation of existing U.S. resources.

AWARD CRITERIA

Applications will compete for available funds with all other approved 
applications assigned to the National Institute of Diabetes and Digestive and 
Kidney Diseases.  The following will be considered in making funding 
decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Leroy M. Nyberg, Jr., Ph.D., M.D., Urology Programs
DKUHD/NIDDK
6707 Democracy Blvd, rm 627
Bethesda, MD 20892-5458
Telephone:  (301) 594-7717
FAX:  (301)-480-3510 
E-mail: NybergL@extra.niddk.nih.gov

or

Monica Liebert, Ph.D., Urology Programs
DKUHD/NIDDK
6707 Democracy Blvd, rm 623
Bethesda, MD 20892-5458
Telephone:  (301) 594-7717
FAX:  (301)-480-3510 
E-mail: liebertm@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ms. Trude Hilliard
Division of Extramural Activities
NIDDK
6707 Democracy Blvd, rm 643
Bethesda, MD 20892
Telephone:  (301) 594-5452
E-Mail: HilliardT@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93. 93.849.  Awards are under authorization of the Public Health Service Act, 
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 
241 and 285) and administered under NIH grants policies and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

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