Full Text HL-93-018

HEMOGLOBIN-BASED OXYGEN CARRIERS:  MECHANISMS OF TOXICITY

NIH GUIDE, Volume 22, Number 29, August 13, 1993

RFA:  HL-93-018

P.T.


Keywords: 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  October 15, 1993
Application Receipt Date:  December 10, 1993

PURPOSE

The Transfusion Medicine Branch, Division of Blood Diseases and
Resources, National Heart, Lung, and Blood Institute (NHLBI), invites
grant applications for studies to elucidate the mechanisms of
toxicity of hemoglobin-based oxygen carriers.

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 Request
for Applications (RFA), Hemoglobin-Based Oxygen Carriers:  Mechanisms
of Toxicity, is related to the priority areas of HIV infection, and
immunization and infectious diseases.  The goal of this program is
the development of safe and effective hemoglobin-based oxygen
carriers free of infectious disease agents.  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 202-782-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of state or local
governments, and eligible agencies of the Federal government.  Awards
in response to this RFA will be made to foreign institutions only for
research of very unusual merit, need, and promise, and in accordance
with PHS policy governing such awards.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant award (R01) and is a one-time solicitation.
Applicants, who will plan and execute their own research programs,
are requested to furnish their own estimates of the time required to
achieve the objectives of the proposed research project.  Up to five
years of support may be requested.  At the end of the official award
period, renewal applications may be submitted for peer review and
competition for support through the regular grant program of the
NHLBI.  It is anticipated that support for the present program will
begin July 1, 1994.  Administrative adjustments in project period or
amount of support may be required at the time of the award.  Since a
variety of approaches would represent valid responses to this
announcement, it is anticipated that there will be a range of costs
among individual grants awarded.  All current policies and
requirements that govern the research grant programs of the NIH will
apply to grants awarded in connection with this RFA.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1994, $1,500,000 will be
available for this initiative.  Approximately $750,000 of that amount
will be provided through an initiative of the Advanced Biomaterials
Program of the Federal Coordinating Council for Science, Engineering
and Technology (FCCSET).  It should be noted that award of grants
pursuant to this RFA is contingent upon receipt of such funds for
this purpose.  It is anticipated that about six to eight new grants
will be awarded under this program.  The specific amount to be funded
will, however, depend on the merit and scope of the applications
received and on the availability of funds.  If collaborative
arrangements involve sub-contracts with other institutions, the NHLBI
Grants Operations Branch (telephone 301/594-7436) should be consulted
regarding procedures to be followed.

RESEARCH OBJECTIVES

Background

An alternative to red blood cells for transfusion has been sought
unsuccessfully for over one hundred years.  In recent years, the
NHLBI and other government agencies have supported research on the
development of stable oxygen carriers that do not need to be
cross-matched and that can be stored for extended periods of time.
During the past decade, awareness of the dangers inherent in
transfusion of allogeneic red blood cells has heightened.  These
include transmission of infectious agents such as HIV, hepatitis
viruses and other microorganisms.  Consequently, physicians are
increasingly reluctant to transfuse their patients and patients are
increasingly reluctant to receive blood.  Although testing of units
of blood is becoming more comprehensive and efficient, there is no
question that products that are free of infectious agents that could
be used in place of red cells would have wide clinical application.
In spite of this promise, studies of hemoglobin-based oxygen carriers
have been disappointing as unpredictable toxicities have thwarted
development of clinically useful products.

Infusion of hemoglobin-based oxygen carriers into the circulation can
result in a variety of outcomes.  Carrier molecules may leave the
circulation by a number of routes including endothelial transcytosis,
phagocytic uptake, and diffusion.  The effects of these materials may
be as diverse as the range of properties of the various tissues they
bathe.  Their interaction with endothelium-derived relaxing factors,
stimulation of other vasoactive materials, and stimulation of
mediators of inflammation may add to the complex biological reactions
noted in research to date.  Furthermore, much of the previous work in
this field is clouded by differences in species, so that, at present,
there are no animal or in vitro models that will reliably predict
human reactions.

In addition to federal support, research and development of
artificial oxygen carriers has been carried out by industry.  Indeed,
industry has contributed valuable knowledge in the area of product
and quality control.  Sophisticated high technology systems have been
developed to produce products in large quantities.  However, in
recent clinical trials with hemoglobin-based oxygen carriers,
unexpected toxicities were observed, suggesting the need for more
basic research to address fundamental questions concerning
interactions with the immune system and endothelium in particular.

Research Objectives and Experimental Approaches

The purpose of this RFA is to encourage research aimed at providing
an understanding of the mechanisms of toxicity of hemoglobin-based
oxygen carriers.  This program encourages research addressing such
fundamental questions as:  (1) what are the mechanisms of
vasoactivity of hemoglobin solutions, (2) how do protein
modifications affect vasoactivity, (3) what are the mechanisms of
stimulation of inflammation mediators by hemoglobin-based oxygen
carriers, (4) how can this stimulation be prevented, (5) what animal
or in vitro models are best used to study toxic effects of oxygen
carriers, (6) what are the long-term (metabolic and pharmacologic)
effects of oxygen carriers, and (7) what models are best to
demonstrate efficacy in terms of oxygen transport to tissue?
Particular encouragement is offered to investigators possessing
modern tools, who are well-trained, and who are currently pursuing
other research interests to devote time and resources to this area.
It is hoped that interdisciplinary and collaborative approaches may
be developed which will complement the efforts of workers in the
field.  The ultimate goal is to satisfy a fundamental need in
clinical medicine, i.e., development of a safe, economical and
efficacious alternative to allogeneic human red blood cells for
transfusion.

Examples of promising topics are:

o  Studies of the interaction of hemoglobin with endothelium and
macrophages.
o  Development of animal models that simulate clinical use, such as
trauma, shock, infection, and surgical blood loss.
o  Studies relating the biochemical modification of hemoglobin to its
biological effects.
o  Studies of encapsulation of hemoglobin into artificial vesicles -
biochemical, physical, physiological, and biological effects.
o  Studies of the tissue distribution and metabolic fate of modified
hemoglobins, and artificial vesicles.

These are intended as examples only.  Investigators are encouraged to
consider other innovative approaches.

Applications may address one or several issues, but should retain a
common theme and focus on addressing those issues.  Because issues
involving hematology, biochemistry, physiology, cell biology,
pharmacology or molecular biology may need to be addressed in a
coordinated manner, collaboration among investigators having
expertise in these and other appropriate disciplines is encouraged.
When individuals are at different institutions, individual R01
applications may include consortium arrangements.

While the main focus of this RFA is on basic or fundamental research
studies to elucidate the mechanisms of toxicity of hemoglobin-based
oxygen carriers, clinical studies, but not clinical trials, are also
appropriate.  Collaborative arrangements with ongoing clinical
studies or trials that provide patient material at little or no cost
to the applicant are also encouraged. Such arrangements should be
clearly delineated in the application.  The description should
include sufficient information to permit scientific evaluation of the
studies proposed.  Among issues to include are the number and type of
specimens/patients, patient population characteristics (including
gender and minority composition; see STUDY POPULATIONS below),
overall goals of the collaborative project, remaining term of the
project, and IRB approval of the project.  If substantial
interactions and costs with ongoing projects are proposed, a
consortium agreement can be developed and submitted to support this
additional research aspect.

If statistical analysis is anticipated, the methodologies and
personnel involved should be described in the application and evident
in the study design.

Exclusions:  Epidemiological studies, large-scale clinical trials,
and large multi-project grant applications (program project grants)
are specifically excluded from this RFA.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage the exchange of information among investigators
who participate in this program.  In the preparation of the budget
for the grant application, applicants should request additional
travel funds for one meeting each year to be held in Bethesda,
Maryland. Applicants should also include a statement in the
applications indicating their willingness to participate in such
meetings.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be 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 should 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 should be provided.

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 should 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, 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, Blacks, and Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (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
minorities.

If the required information is not contained within the application,
the application 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 NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 15, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Such letters are requested
only for the purpose of providing an indication of the number and
scope of applications to be received; therefore their receipt is
usually not acknowledged.  A letter of intent is not binding, and it
will not enter into the review of any application subsequently
submitted, nor is it a necessary requirement for the application.
This letter of intent is to be sent to:

Chief, Centers and Special Projects Review Section
Division of Extramural Affairs
Natinal Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 594-7448
FAX:  (301) 594-7407

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form PHS 398 (rev. 9/91). This form is available in an applicant
institution's office of sponsored research or business office and
from the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone (301) 435-0714.  Use the conventional
format for research grant applications and ensure that the points
identified in the section on REVIEW CONSIDERATIONS are fulfilled.  To
identify the application as a response to this RFA, check "YES" on
Item 2a of page 1 of the application and enter the title and RFA
number:  HEMOGLOBIN-BASED OXYGEN CARRIERS: MECHANISMS OF TOXICITY:
NHLBI RFA HL-93-018-B.  The RFA label available in the PHS 398
application kit must be affixed to the bottom of the face page of the
original copy of the application.  Failure to use this label could
result in delayed processing of the application.

Send or deliver the completed application and three signed, exact
photocopies to the following, making sure that the original
application with the RFA label attached is on top:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send an additional two copies of the application to the Chief,
Centers and Special Projects Review Section at the address listed
under LETTER OF INTENT.  It is important to send these two copies at
the same time as the original and three copies are sent to the
Division of Research Grants.  Otherwise the NHLBI cannot guarantee
that the application will be reviewed in competition for this RFA.

Applications must be received by December 10, 1993.  If an
application is received after that date, it will be returned to the
applicant without review. The DRG will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction
addressing the previous critique.

This is a National Heart, Lung, and Blood Institute Request for
Applications.  the National Institute of Environmental Health
Sciences (NIEHS) also has an interest in the subject matter of this
announcement and therefore, may be given a secondary institute
assignment, if appropriate.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NHLBI staff will contact
the applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an NHLBI peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review. Those applications that
are complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the Division of Extramural
Affairs, NHLBI.  The second level of review will be provided by the
National Heart, Lung, and Blood Advisory Council.

Review Criteria

The factors to be considered in the evaluation of scientific merit of
each application will be similar to those used in the review of
traditional research grant applications, including the novelty,
originality, and feasibility of the approach; the training,
experience and research competence of the investigator(s); the
adequacy of the experimental design; the suitability of the
facilities; and the appropriateness of the requested budget to the
work proposed.

AWARD CRITERIA

The anticipated date of award is July 1, 1994.  Funding decisions
will be made on the basis of scientific and technical merit as
determined by peer review, program needs and balance, and the
availability of funds.

Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.

INQUIRIES

Written and telephone inquiries concernint htis RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Dr. George J. Nemo
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 504
Bethesda, MD  20892
Telephone:  (301) 496-1537
FAX:  (301) 402-4843

Inquiries regarding fiscal and administrative matters may be directed
to:

Ms. Jane R. Davis
Blood Division Grants Management Section
National Heart, Lung, and Blood Institute

Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7436

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance number
93.839.  Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS
grant policies and Federal regulations, most specifically 42 CFR Part
52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372, or to
Health Systems Agency review.

.

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