NIH GUIDE, Volume 21, Number 35, October 2, 1992

PA NUMBER:  PA-93-002

P.T. 34


  Diagnosis, Medical 

  Biology, Molecular 


National Institute of Diabetes and Digestive and Kidney Diseases


The purpose of this Program Announcement (PA) is to encourage research

on isolating the gene(s) or the full length cDNAs for the gene(s) of

the many genetic liver diseases in which early diagnosis and treatment

could avert progressive serious liver injury.  Liver transplantation is

often the only treatment for these diseases when they are not detected

and treated early.  Two of the liver diseases in which early diagnosis

could be curative and in which much information exists about the gene

and/or its location are Wilson's disease and hemochromatosis.


The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This PA,

Prevention of End Stage Liver Diseases by Molecular diagnosis, is

related to the priority area of diabetes and chronic disabling

conditions.  Potential applicants may obtain a copy of "Healthy People

2000" (Full Report:  Stock No. 017-001-00474-0) or Healthy People 2000"

(Summary Report:  Stock No. 017-001-00473-1) through the Superintendent

of Documents, Government Printing Office, Washington, DC 20402-9325

(telephone 202-783-3238).


Applications may be submitted by domestic for-profit and non-profit

United States organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) Awards (R29).


The Research Project Grant (R01), the FIRST Award (R29), and the

Interactive Research Project Grant (interactive R01s) are all

appropriate mechanisms.  Program Project Grant (P01) or Center Grant

(P30) applications will not be accepted.


Hemochromatosis and Wilson's disease are two inherited diseases of

trace metal metabolism that can cause end stage liver disease.  If

diagnosed early before the onset of significant liver damage, available

treatments are usually effective.  Unfortunately, both hemochromatosis

and Wilson's disease are rarely diagnosed before the onset of symptoms

in the liver or other organs.  Both diseases result in liver cirrhosis

for which liver transplantation is the only effective treatment.

Currently, there is no easy means of early screening for either disease

since the genetic defect has not been positively identified.

Hemochromatosis, which affects approximately one in 300 persons,

appears to be due to an excessive absorption of dietary iron that leads

over years to excessive bodily iron stores that eventually cause

cellular damage and organ injury in liver, heart, pancreas and gonads.

If hemochromatosis is diagnosed, the organ injuries can be averted by

phlebotomy to decrease the body iron stores to normal.  The enzyme or

transport protein responsible for the excessive absorption of iron has

not been identified.  It is not ferritin, transferrin, or the

transferrin receptor.  The new techniques of molecular biology promise

to provide means of identifying the defect in hemochromatosis.  The

molecular techniques needed are probably not the conventional ones that

proceed from the abnormal protein to the gene, but rather "reverse

genetics" that first identifies the gene and from it the abnormal

protein.  Such techniques were successful in identifying the

abnormality in cystic fibrosis and neurofibromatosis.  Indeed, in

hemochromatosis an advantage has been established already by the known

linkage of this disorder with the HLA region on the short arm of

chromosome 6.  If the gene for hemochromatosis could be identified,

genetic screening of newborns could be used to identify homozygotes and

to initiate lifelong phlebotomy therapy before the onset of disease or

organ damage.

Wilson's disease, which affects approximately one in 10,000 persons,

appears to be due to a genetic defect in the secretion of copper in

bile that leads over time to a gradual accumulation of excessive copper

stores in the liver, red blood cells, synovium, kidneys and brain.

Untreated Wilson's disease leads to irreversible end stage liver

disease and/or brain damage between the ages of 15 and 40 years.  If

Wilson's disease can be identified early, however, the copper

accumulation can be prevented by chelation therapy (d-penicillamine)

and the liver and brain disease completely averted.  Unfortunately,

Wilson's disease is rarely diagnosed early, and this is still an

important cause of liver failure necessitating liver transplantation.

Approaches that might be taken to identify the Wilson's disease gene

also include those of reverse genetics by identifying genetic markers

that co-segregate with this disease.  Such studies require data

collected from large families with Wilson's disease using multiple

genetic markers.  These studies have shown that this gene is located on

chromosome 3.  Further studies are needed to more closely locate the

gene to a fragment of DNA that can be sequenced and characterized.

Both of these examples of diseases that could benefit from appropriate

early diagnosis through molecular biology techniques require the

availability of large family cohorts to serve as subjects and controls.

The availability of multi-generational families in which linkage

analyses can be done will be very important to progress in these


Other liver diseases such as Alagille syndrome and Crigler-Najjar

syndrome type I, in which early diagnosis may make available

treatment(s) that can prevent serious liver malfunction, may also be

submitted and be responsive to this PA.  The emphasis in this

announcement is on the diagnosis of the genetic defect and not on the

treatment of the disease.





It is NIH policy that women and minorities must be included in clinical

study populations unless there is a good reason to exclude them, and

the study design must seek to identify any pertinent gender or minority

population differences.

NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women in

study populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis must be placed on the need for inclusion of minorities

and women in studies of diseases, disorders and conditions which

disproportionately affect them.  This policy is intended to apply to

males and females of all ages.  If women or minorities are excluded or

inadequately represented in clinical research, particularly in proposed

population-based studies, a clear compelling rationale must be


The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues must be addressed in developing a research design

and sample size appropriate for the scientific objectives of the study.

This information must be included in the form PHS 398 (rev. 9/91) in

Sections 1-4 of the Research Plan AND summarized in Section 5, Human

Subjects.  Applicants are urged to assess carefully the feasibility of

including the broadest possible representation of minority groups.

However, the NIH recognizes that it may not be feasible or appropriate

in all research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for studies

on single minority population groups must be provided.

For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(and preventive strategies), diagnosis, or treatment of diseases,

disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.

All applications for clinical research submitted to the NIH are

required to address these policies.  NIH funding components will not

award grants or cooperative agreements that do not comply with these



Applications are to be submitted on the grant application form PHS 398

(rev. 9/91) and will be accepted at the regular application deadlines

as indicated in the application kit.

FIRST (R29) Award applications must include at least three sealed

letters of reference attached to the face page of the original

application.  FIRST Award applications submitted without the required

number of reference letters will be considered incomplete and will be

returned to the applicant without review.

Application kits are available at most institutional business and

grant/contract offices and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of Health,

Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/496-

7447.  The title and number of this announcement must be typed in

Section 2a on the face page of the application.

The completed original application and five legible copies must be sent

or delivered to:

Division of Research Grants

National Institutes of Health

Westwood Building Room 240

Bethesda, MD  20892**


Applications will be assigned to initial review groups and to

Institutes or Centers for possible funding on the basis of established

PHS referral guidelines.  Applications will be reviewed for scientific

and technical merit by initial review groups of the Division of

Research Grants in accordance with the standard NIH peer review

procedures.  Following scientific-technical review, the applications

will receive a second-level review by an appropriate National Advisory



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Sarah C. Kalser, Ph.D.

Liver and Biliary Diseases Program Director

Division of Digestive Diseases and Nutrition

National Institute of Diabetes and Digestive and Kidney Diseases

5333 Westbard Avenue, Room 3A-05

Bethesda, MD  20892

Telephone:  (301) 496-7858

David G. Badman, Ph.D.

Hematology Program Director

Division of Kidney, Urologic, and Hematologic Diseases

National Institute of Diabetes and Digestive and Kidney Diseases

5333 Westbard Avenue, Room 3A-05

Bethesda, MD  20892

Telephone:  (301) 496-7458

Direct inquiries regarding fiscal matters to:

Miss Aretina Perry

Grants Management Branch

National Institute of Diabetes and Digestive and Kidney Diseases

Bethesda, MD  20892

Telephone:  (301) 496-7467


This program is described in the Catalog of Federal Domestic Assistance

No. 93.848.   Awards are made 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 PHS grants

policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This

program is not subject to the intergovernmental review requirements of

Executive Order 12372 or Health Systems Agency review.


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