CALCIUM OXALATE STONE DISEASES

RELEASE DATE:  January 30, 2003

PA NUMBER: PA-03-065

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. A replacement R21 (PA-06-152) and R01 (PA-06-153)
funding opportunity announcements have been issued for the submission date of June 
1, 2006 and submission dates thereafter.

See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and 
AIDS-related R03 and R21 Applications.

EXPIRATION DATE:  March 2, 2006

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
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 Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

Urinary tract stone disease constitutes a major health care burden for the 
United States population, causing significant pain, morbidity, and 
hospitalization.  Recent reports suggest that the incidence of these cases is 
increasing.  The majority of urinary tract stones are composed of calcium 
oxalate.

Genetic studies have identified a small group of individuals with known 
inherited metabolic disorders who develop recurrent calcium oxalate stones at 
a very early age.  Most of these persons have genetic disorders, called 
Primary Hyperoxalurias (PHs), which cause defective regulation of oxalate 
synthesis in the liver, leading to an excessive excretion of oxalate in the 
urine and the subsequent development of urinary tract stones. 

The genetic contribution to development of the other, more prevalent, calcium 
oxalate stone diseases of adults is unknown.  Previous studies suggest a 
familial incidence in a subset of persons who have recurrent urinary tract 
stone disease.  Identification and characterization of families of recurrent 
stone formers is essential for the identification of unique genetic, 
environmental and metabolic factors that predispose individuals to recurrent 
calcium oxalate stone formation. Most importantly, novel and previously 
unexplored approaches for the effective treatment and prevention of the 
calcium oxalate urinary tract stone diseases are needed.  

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, and to develop new treatments for the disorder.  This 
initiative solicits research as well as pilot and feasibility studies that 
utilize new and innovative approaches to study the diagnosis, treatment and 
prevention of these disorders.   The Division of Kidney and Urologic and 
Hematologic Diseases of the NIDDK has identified this initiative as one of a 
subset of active program announcements (PAs) that are high priority, and 
warrant a set-aside of NIDDK "Special Emphasis" funds (see 
http://grants.nih.gov/grants/guide/notice-files/NOT-DK-03-001.html).  

RESEARCH OBJECTIVES

A. Background

Although calcium oxalate stone disease is a very common health problem among 
adults in the United States, it is poorly understood at the basic science 
level.  Previous work has suggested that this disease tends to occur within 
families but pedigrees have not been well established or studied.

There are several rare, heritable causes of nephrolithiasis that result in 
the onset of oxalate stone disease early in childhood and frequently lead to 
renal failure.  The primary hyperoxalurias (PHs) are known to be due to 
mutations affecting hepatic enzymes that metabolize glyoxylate.  The non-
catabolized glyoxylate is oxidized to oxalate and is excreted in excess in 
the urine.  Dent's disease, also known as X-linked recessive nephrolithiasis, 
is a hereditary condition characterized by hypercalciuria, nephrocalcinosis, 
and kidney stones.  The disease also causes proteinuria, progressive renal 
failure, and, in some patients, rickets. It is associated with mutations that 
inactivate the voltage-gated chloride channel ClC-5

In 2002, the NIDDK sponsored two workshops to discuss aspects of hereditary 
calcium oxalate stone disease.  The first, "Hepatocyte-Based Therapies for 
Oxalosis," was held in June 2002, and focused on the challenges of correcting 
the hepatic cell enzymatic defect in primary hyperoxaluria that leads to the 
impairment of the kidney and other organs, but not the liver.  The second, 
"Hereditary Calcium Oxalate Stone Disease Registry Planning Meeting," 
discussed the need to establish a high-quality registry with detailed data 
about patients with hereditary calcium oxalate stone diseases.

Both meetings highlighted the need for new and innovative research on the 
molecular etiology (or etiologies) of hereditary calcium oxalate stone 
disease, as well as for novel and effective treatments and preventive 
strategies.  Similarly, there is a need for research to elucidate the 
etiology, risk factors, or genetic basis of idiopathic forms of the disease.  
This announcement focuses on oxalate stone disorders in an attempt to better 
understand the metabolic, molecular, and genetic defects responsible for the 
disease and to eventually develop more effective diagnosis, treatment and 
preventive strategies.

B. Objectives and Scope 

It is the intent of this program announcement to increase novel and 
productive research focusing on primary hyperoxaluria, Dent's Disease and the 
recurrent oxalate stone diseases and to encourage both new and experienced 
investigators from related fields of research to apply their knowledge and 
skills to this area.  

Research topics which are included within the scope of this announcement 
include, but are not limited to:

o development of strategies to identify, characterize and investigate family 
pedigrees with spontaneous calcium oxalate stone disease to study risk 
factors, genetic defects, environmental factors and other related factors.

o identification and characterization of genetic modifier loci that influence 
the progression of primary hyperoxaluria, Dent's Disease or other heritable 
recurrent calcium oxalate stone diseases.

o development of new or improved animal models for the study of human 
hereditary and idiopathic calcium oxalate stone diseases, including 
transgenic animals with conditional mutations

o improvement of tools for prenatal or post-natal diagnosis

o development of novel strategies to replace, correct, prevent or ameliorate 
the effects of the genetic defect identified in primary hyperoxaluria or 
Dent's Disease, including the use of hepatocyte transplantation

o studies of methods to correct defective processing, folding or organelle 
targeting of mutant enzymes

o clarification of the etiologic factors for development of oxalate stone 
disease in patients with bowel disease and identification of improved 
prevention and therapy options in this patient population

o identification of gene expression patterns that are related to the etiology 
of calcium oxalate nephrolithiasis using microarray, SAGE, or other 
technologies

o elucidation of the molecular events underlying disease progression, 
including identification of biomarkers that signal susceptibility to 
development of the disease or specific complications

MECHANISM(S) OF SUPPORT 

This PA will use the NIH R01 (investigator-initiated research project grant) 
and the R21 (exploratory/developmental research grant) award mechanisms.  The 
R01 mechanism is recommended for applications that propose research for which 
preliminary data exists. As an applicant you will be solely responsible for 
planning, directing and executing the proposed project. 

The R21 award is an exploratory/developmental research grant for support of 
high-risk pilot and feasibility research designed to develop new ideas 
sufficiently to allow future submission of a full R01 application.  See 
http://www.niddk.nih.gov/fund/grants_process/revmech.htm for a description of 
R21 awards.  R21 grants awarded through this PA will provide up to $275,000 
over two years in direct costs, with a maximum of $175,000 direct costs in 
any one year, and may not be renewed. The Research Plan section of an R21 
application should not exceed 15 pages. 

Applicants are encouraged to contact program staff for information about 
choosing the appropriate grant mechanism.

This PA 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.  If the direct costs of your application are 
greater that $250,000 follow the instructions for non-modular research grant 
applications.

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 

For the duration of their award, investigators must participate in yearly 
meetings and periodic conference calls organized by the NIH and designed to 
facilitate the exchange of ideas and findings. 

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Rebekah S. Rasooly, Ph.D.
Program Director, Genetics and Genomics
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 643
Bethesda, MD  20892-5458
TEL:  (301) 594-6007
FAX:  (301) 480-3510
Email:  rr185i@nih.gov 
 
o Direct your questions about financial or grants management matters to:

Trude Hilliard
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 717
Bethesda, MD 20892
Telephone:  (301) 451-8859
FAX:  (301) 480-4237
Email:  th105x@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 Grants Info, Telephone: (301) 435-
0714, E-mail: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTION FOR R21 APPLICATIONS: All application instructions 
outlined in the PHS 398 application kit are to be followed, with the 
following requirements for R21 applications:  

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the total 
direct costs limit of $175,000 per year. 

2.  Although preliminary data are not required for an R21 application, they 
may be included.

3.  Sections a-d of the Research Plan of the R21 application may not exceed 
15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.   Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o   Up to five publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project.  These may be stapled as sets.
o   Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o   Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included 
within the 15-page limit of items a-d of the research plan.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications 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.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
R01 applications requesting $500,000 or more in direct costs for any one 
year must get prior approval from NIH before submission, by carrying out the 
following steps:

1) Contact the IC program staff at least 6 weeks before the submittal 
deadline;
2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm. The 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.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the National Diabetes and Digestive and 
Kidney Diseases Advisory 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:

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.

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)

DATA SHARING:  The adequacy of the proposed plan to share data. Investigators 
receiving awards will be required to generate a data-sharing plan. This plan 
will be reviewed for: statements of willingness to share information fully; 
clarity of included Material Transfer Agreements and Reagent and Animal 
Transfer Agreements; adequate and clear strategies for sharing results/data, 
tools, and mice with the research community and/or websites maintained by the 
NIH.

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

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

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://grants1.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. 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

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

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

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

Applicants may wish to place data collected under this PA 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 PA 
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. 93.849 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


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