PHYSIOLOGY AND PATHOLOGY OF LOW CHOLESTEROL STATES

NIH GUIDE, Volume 23, Number 15, April 15, 1994



PA NUMBER:  PA-94-057



P.T. 34



Keywords:

  Cardiovascular Diseases 

  Pathophysiology 

  Social Psychology 

  Biochemistry, Lipids 

  Genetics 



National Heart, Lung and Blood Institute

National Institute on Aging



PURPOSE



The purpose of this program announcement is to foster research that

will improve the understanding of low cholesterol states in health

and sickness.  Applications are sought for basic and applied research

drawing from the disciplines of biochemistry, physiology, pathology,

genetics, nutrition, clinical medical sciences, and psychosocial

(behavioral) sciences.



HEALTHY PEOPLE 2000



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 program

announcement, Physiology and Pathology of Low Cholesterol States, is

related to the priority area of heart disease and stroke.  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).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal Government.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.  Applications from

minority individuals and women are encouraged.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC as a resource for conducting

the proposed research.  If so, a letter of agreement from either the

GCRC program director or principal investigator could be included

with the application.



MECHANISM OF SUPPORT



This program seeks applications for research project grants (R01) and

FIRST awards (R29).  Because the nature and scope of the research

proposed in response to this PA may vary, it is anticipated that the

size of awards will vary as well.



RESEARCH OBJECTIVES



Background



Interest in low cholesterol states has increased in recent years.

The final report of the 1990 NHLBI workshop on Low Cholesterol:

Mortality Associations (Circulation 1992; 86:1046-1060) described how

a large number of observational epidemiological studies show a

consistent J-shaped curve relationship between total cholesterol

level and total mortality risk, with increased mortality rates

observed in males having very low cholesterol levels (120-140 mg/dL

and below).  The interpretation of the J-shaped curve was difficult,

however, because observational studies do not collect the type of

data needed to clarify the biological basis of this phenomenon.

Similarly, the degree to which the curve reflects underlying

confounding could not be determined.



The J-shaped curve observation has been used to buttress arguments

that there are risks of noncardiovascular illness and death

associated with the cholesterol-lowering approaches advocated for the

prevention of cardiovascular disease in populations.  This school of

thought, particularly prevalent in Europe and the United Kingdom, but

also advocated in the United States, extrapolates that phenomena

responsible for the U-shaped curve also apply to the upper half of

the plasma cholesterol distribution, where cholesterol-lowering

efforts are directed.  Given the great effort that has been put

towards research and public education programs regarding the expected

benefits of cholesterol lowering, this issue must be considered

seriously.



It has been difficult to reconcile the concerns expressed about

cholesterol lowering with most of the other data on low cholesterol

conditions. Healthy animals eating diets in the wild usually have low

cholesterol levels.  Some of the human populations living under

circumstances of adequate sanitation (in Japan, for example) are

known to consume relatively low fat, low cholesterol diets compatible

with both low blood cholesterol levels and generally good health.

Some individuals simply maintain low cholesterol levels despite

eating a high fat diet.  Individuals with hypobetalipoproteinemia

usually appear to enjoy good health and some markedly long-lived

kindreds have been described.  At the same time, it is clear that a

low cholesterol level can be caused not only by certain genetic

conditions, but also can be an epiphenomenon of conditions such as

weight loss, infection, hyperthyroidism, liver disease, anemia,

malabsorption and certain types of cancer.  In geriatric patients

with severe weight loss and markedly elevated mortality risk, it is

unclear whether the hypocholesterolemia that often accompanies this

reflects an underlying pathophysiologic cause or is an epiphenomenon.

What makes the hypocholesterolemia of good health different from that

of illness?



Proposed Research



This program announcement seeks to elicit a diverse group of

applications to explore the biology and pathophysiology of low

cholesterol conditions.  A consortium arrangement may be necessary to

support inter-institutional research collaboration.  Well-designed

studies proposing hypothesis-testing research in humans and animals

are preferred.



Potential areas for investigation could include, but are not limited

to, the following:



o  Studies of hypobetalipoproteinemic kindreds and individuals,

including genetic, metabolic, clinical and psychosocial studies.



o  Studies of other low cholesterol states, including low cholesterol

associated with various co-morbid conditions, and the mechanisms

whereby they arise.



o  Studies in transgenic animal models, especially those that

preserve a low plasma cholesterol level when fed diets that usually

are hypercholesterolemic.



o  Studies, particularly in humans, of the mechanisms underlying of

the hyporesponse to high fat, high cholesterol diets.



o  Studies yielding reliable estimates of the frequency of

hypocholesterolemia due to various causes.



o  Studies on causes and pathophysiologic significance of

hypocholesterolemia in geriatric patients with severe weight loss,

including its relationship to nutritional and other metabolic

factors.



STUDY POPULATIONS



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 is provided

that inclusion is inappropriate with respect to the health of the

subjects or the purpose of the research.  This new policy results

from the NIH Revitalization Act of 1993 (Section 492B of Public Law

103-43) and supersedes and strengthens the previous policies

(Concerning the Inclusion of Women in Study Populations, and

Concerning the Inclusion of Minorities in Study Populations), which

have been in effect since 1990. The new policy contains some

provisions that are substantially different from the 1990 policies.



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 9, 1994 (FR 59 11146-11151) and reprinted

in the NIH Guide for Grants and Contracts, Volume 23, Number 11,

March 18, 1994.



Investigators also may obtain copies of the policy 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. 9/91) 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 and may be obtained from the Office of Grants

Information, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

(301) 710-0267.  The title and number of this program announcement

must be typed in Section 2a on the face page of the application.



Applications for the FIRST Award (R29) must include at least three

sealed letters of reference attached to the face page of the original

application.  FIRST Award (R29) applications submitted without the

required number of reference letters will be considered incomplete

and will be returned without review.



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**



REVIEW CONSIDERATIONS



Applications will be assigned on the basis of established PHS

referral guidelines.  Applications will be reviewed for scientific

and technical merit by study sections of the Division of Research

Grants, NIH, in accordance with the standard NIH peer review

procedures.



Following scientific-technical review, the applications will receive

a second-level review by the appropriate national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other

applications assigned to that ICD.  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 balance among research areas of the announcement



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Dr. Abby G. Ershow

Division of Heart and Vascular Diseases

National Heart, Lung, and Blood Institute

Federal Building, Room 401

Bethesda, MD  20892

Telephone:  (301) 496-1681

FAX:  (301) 496-9882



Dr. Pamela E. Starke-Reed

Office of Nutrition

National Institute of Aging

Gateway Building, Suite 2C231

Bethesda, MD  20892

Telephone:  (301) 496-6402

FAX:  (301) 402-0010



Direct inquiries regarding fiscal matters to:



Mr. William Darby

Division of Extramural Affairs

National Heart, Lung, and Blood Institute

Westwood Building, Room 4A11

Bethesda, MD  20892

Telephone:  (301) 594-7458

FAX:  (301) 594-7492



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.837.  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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