Expired PA-03-065: CALCIUM OXALATE STONE DISEASES

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

This notice has expired. Check the NIH Guide for active opportunities and notices.

EXPIRED

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) 710-0267, 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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