Subject: NIH GUIDE - RFA HL-92-05-B - V20(42) 11/08/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Mon, 11 Nov 91 12:46 EST

Hi Paul,
This is the second part of this week's NIH Guide.  Please
post to the NIH Listserver as:
RFAHL9205B.911108.
  Thanks, M. G. Broaddus
 ---------------------------- Text of forwarded message -----------------------
 
ALZHEIMER'S AMYLOID BETA PROTEIN PRECURSOR IN HEMOSTASIS AND THROMBOSIS
 
RFA:  HL-92-05-B
 
P.T. 34; K.W. 0715180, 0715040, 1002008, 0755030
 
National Heart, Lung, and Blood Institute
National Institute on Aging
 
Letter of Intent Receipt Date:  February 15, 1992
Application Receipt Date: March 16, 1992
 
This Request for Applications (RFA) is jointly sponsored by the
National Heart, Lung, and Blood Institute (NHLBI) and the National
Institute on Aging (NIA), because both Institutes have an interest in
this area of research.  All applications submitted in response to this
RFA will be assigned to both Institutes for funding consideration.
However, the primary Institute assignment will be made to the Institute
that has the more specific interest in the research proposed.
 
PURPOSE
 
The Division of Blood Diseases and Resources, NHLBI, and the
Neuroscience and Neuropsychology on Aging Program, NIA, invite grant
applications for a single competition for support of research on the
biochemistry and molecular biology of the beta amyloid precursor
protein.  The emphasis of this research is on the possible involvement
of this protein in the function or dysfunction in hemostasis and
thrombosis.  It is hoped that the information generated will further
the understanding of the molecular pathology of Alzheimer's disease and
Downs syndrome.
 
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 RFA,
Alzheimer's Amyloid Beta Protein Precursor in Hemostasis and
Thrombosis, is related to the priority areas of thrombosis and
Alzheimer's disease.  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).
 
DISCIPLINES AND EXPERTISE
 
Among the disciplines and expertise that may be appropriate for this
program are hematology, biochemistry, neurology, cell biology,
immunology, and molecular biology.
 
SCIENTIFIC BACKGROUND
 
Alzheimer's disease is an idiopathic progressive dementia affecting a
large proportion of our aging population.  The major proteinaceous
component of the amyloid deposits that accumulate extracellularly in
the brains of patients with Alzheimer's disease is the amyloid beta
protein (AbP or A4).  The AbP is a peptide composed of approximately 40
amino acid residues and is derived from a larger protein, the amyloid
beta protein precursor (APP). The AbP appears to consist of the 28
amino acids just outside the membrane plus the 11 to 14 residues of the
hydrophobic transmembrane domain of APP.  APP is found in human brain,
cerebrospinal fluid, kidney, spleen, heart and adrenal tissues, but not
in blood erythrocytes or leukocytes.  It is likely that both AbP and
APP are heterogeneous proteins.
 
There are several alternatively spliced APP transcripts.  The two most
abundantly expressed forms contain a 56- residue insert that has
significant homology with the Kunitz serine protease inhibitor.  APP
has been shown to be an inhibitor of serine proteases and has been
claimed to posses growth factor activity.  Thus, an intricate protease
regulatory mechanism may be involved in the release and deposition of
AbP in the extracellular space. Younger subjects with Down syndrome
show diffuse AbP deposits in the absence of surrounding neuronal and
glial dystrophy while older subjects with Down syndrome develop
classical senile plaques indistinguishable from Alzheimer's disease.
These observations provide strong evidence that diffuse AbP deposition
may be an early event and may precede the cytopathology of Alzheimer's
disease.
 
Several recent observations provide compelling evidence that APP may
have a broader role and, in fact, may be involved in hemostasis and
thrombosis.  Research on hematologic aspects of APP may actually
contribute to a better understanding and treatment of Alzheimer's
disease. Human platelet granules have now been found to contain a
significant amount of APP.  When platelets are activated, this protein
is secreted and may inhibit proteases in the extracellular space.  That
APP may have protease inhibitory activity was actually defined when the
secreted form of APP was found to be identical to the platelet protein,
protease nexin 2 (PN-2).  PN-2 has previously been isolated and shown
to promote cell adhesion.  Yet another alteration in proteolytic
mechanisms that may occur in Alzheimer's disease involves the protease
inhibitor, protease nexin 1 (PN-1).  This protein was initially
described as a glial-derived neurite promoting factor and is also
present in platelets.  PN-1 is a potent inhibitor of thrombin, the
central enzyme involved in platelet activation and blood coagulation,
that causes neurite retraction.  Recent studies show that PN-1 is
reduced about seven-fold in Alzheimer's disease brain compared to brain
tissue in age matched controls.  Thus, there is an imbalance between
thrombin and PN-1 in the Alzheimer's disease brain.  Platelet APP/PN-2
is a potent inhibitor of coagulation factor XIa, trypsin, and
chymotrypsin but has little activity against other coagulation or
fibrinolytic enzymes.  In the presence of heparin, the inhibition of
FXIa is enhanced by about 15- fold without any effect on the inhibition
of trypsin or chymotrypsin.  Thus, APP might have a regulatory role on
the intrinsic pathway of coagulation similar to extrinsic pathway
inhibitor or lipoprotein-associated coagulation inhibitor on the
extrinsic pathway.
 
Strong evidence for the support of a role of APP in
hemostasis-thrombosis came from studies in four Dutch families with an
autosomal dominant form of hereditary cerebral hemorrhage with
amyloidosis (HCHWA-D).  The amyloid deposits in this disease contain a
form of AbP and resemble the diffuse plaques of Alzheimer's disease.
Genetic linkage analysis in two of these Dutch families show that the
APP gene is tightly linked to HCHWA-D, suggesting that a mutation in
APP is responsible for this pathological condition.  A point mutation
in the coding region of APP in two Dutch patients, glutamine for
glutamic acid at position 22 of AbP, has now been confirmed.  Since no
such substitution has been found in the general population, this
mutation is unlikely to be an irrelevant polymorphism and has been
proposed to be the primary defect in HCHWA-D.
 
The human platelet has long been used as a peripheral model for
neurons.  The demonstration of abnormalities of morphology and function
of platelets in Parkinson's disease, Huntington's disease, and
depression suggests that altered neuronal function in specific diseases
may be reflected in the platelet.  In fact, it has now been shown that
the amyloid precursor protein of Alzheimer's disease is released by
activated blood platelets, and the association of megakaryoblastic
leukemia with Down syndrome should be reevaluated.
 
Examples of Research
 
The following are only examples and prospective applicants are urged to
use their own ideas for the area of research.
 
o  Platelets appear to be the only cell in blood or in the vasculature
that contain APP in granules in a significant concentration.  What is
the source of this APP?  How is APP proteolytically processed, what
proteases are involved and is this processing different in Alzheimer's
compared to normal?  Could this APP be the source of AbP observed in
the vasculature or plaques of patients?  The possibility that a
platelet membrane abnormality affects APP release and the consequent
production of an amyloidogenic fragment warrants further investigation.
 
o  Proteases and their inhibitors are known to be intimately involved
in platelet function, blood coagulation, and fibrinolysis.  Basic
information on the processing of APP and the insertion/deletion of the
inhibitor domain may contribute to our understanding of hematology and
wound healing. That APP selectively inhibits FXIa suggests yet another
mechanism by which platelets may regulate intrinsic coagulation.
 
o  In view of the improved understanding of the cell biology and
molecular biology of platelets, determination of the functional status
of platelets in this pathological condition remains desirable.  Altered
expression of platelet membrane component(s) could be useful in
identifying those at risk for developing Alzheimer's disease.  The
expression, structure, and processing of APP in megakaryocytes and
platelets need to be better defined.
 
o  Is APP a soluble component of alpha granules or is it membrane
located? Is platelet APP normal in Alzheimer's disease?  Upon platelet
activation, is APP secreted to the extracellular space or is it
transferred to the platelet surface where it acts as a receptor or is
it both?  How does this process compare with other platelet alpha
granule proteins such as PF4 or PADGEM?
 
o  Do the various forms of APP have different growth factor activities
and/or different effects on vascular cells or in wound healing?  Are
different forms of the alternatively spliced APP mRNAs expressed in
different tissues?
 
o  The normal biological role of APP in various cells has not been
established.  Does APP have a different functional role in blood cells
and in brain parenchymal cells?
 
o  Based on the knowledge gained on the role of APP in platelet
function and blood coagulation, it may be possible to develop a simple
test for the diagnosis and prognosis of Alzheimer's disease.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 should be included in the form PHS 398 in
Section 2, A-D of the Research Plan AND summarized in Section 2, E,
Human Subjects.  Applicants/offerors 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 (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, 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 returned.
 
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.
 
EXCLUSIONS
 
Epidemiological studies and large-scale clinical trials are
specifically excluded from this RFA.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the traditional,
individual, research project grant (R01).  Although the financial plans
for fiscal year 1992 include $1.0 million for the NHLBI and $1.5
million for the NIA, award of grants pursuant to this RFA is contingent
upon receipt of funds for this purpose.  It is anticipated that up to
twelve grants will be awarded by NHLBI (five) and NIA (seven) 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. 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.  If collaborative
arrangements involve sub-contracts with other institutions, the NHLBI
Grants Operations Branch (telephone:  301/496-7257) or NIA Grants
Management Branch (telephone:  301/496-1472) must be consulted
regarding procedures to be followed.  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 may be submitted by 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.  Applications from
minority individuals and women are encouraged.
 
Upon initiation of the program, the NHLBI and the NIA 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 must REQUEST
ADDITIONAL TRAVEL FUNDS for one meeting each year to be held in
Bethesda, Maryland.
 
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 grant program of the NHLBI or NIA.
It is anticipated that support for the present program will begin in
September 1992.  Administrative adjustments in project period and/or
amount of support may be required at the time of the award.  All
current policies and requirements that govern the research grant
programs of the National Institutes of Health will apply to grants
awarded in connection with this RFA.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method:  Applications will be reviewed for their responsiveness
to the objectives of this RFA.  If an application is judged
unresponsive, the application will be returned to the applicant.
If the application submitted in response to this RFA is
substantially similar to a grant application already submitted to the
NIH for review, but has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be allowed,
nor will essentially identical applications be reviewed by different
review committees.  Therefore, an application cannot be submitted in
response to this RFA that is essentially identical to one that has
already been 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.
 
Applications judged to be responsive will be reviewed for scientific
and technical merit by an initial review group that will be convened by
the Division of Extramural Affairs, NHLBI, solely to review these
applications.
 
This initial review will include a preliminary evaluation to determine
scientific merit relative to the other applications received in
response to the RFA (triage).  The NIH will withdraw from further
consideration applications judged to be noncompetitive and promptly
notify the Principal Investigator/program director and the official
signing for the applicant organization.  Those applications judged to
be competitive will be further evaluated for scientific/technical merit
by the usual peer review procedures, including, if deemed appropriate,
a reverse site visit at the applicant's expense.
 
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-project 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.
 
METHOD OF APPLYING
 
Letter of Intent:  Prospective applicants are requested to submit a
letter of intent that includes a descriptive title of the proposed
research and identification of any other participating institutions.
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 publication.  This letter of intent is to be received by February
15, 1992, and is to be sent to:
 
Dr. Charles L. Turbyfill
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
Westwood Building, Room 553
Bethesda, MD  20892
 
Format for Applications:  Applications must be submitted on the
traditional research-project grant application form PHS 398 (rev.
10/88).  This form is available in an applicant institution's office of
sponsored research or business office and from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
Room 449, 5333 Westbard Avenue, Bethesda, MD 20892, telephone 301/496-
7441.  Use the conventional format for research-project grant
applications and ensure that the points identified in the Section on
"Review Procedures and Criteria" are fulfilled.
 
To identify the application as a response to this RFA, check "YES" on
Item 2 of page 1 of the application and enter the title and RFA Number:
 
"ALZHEIMER'S AMYLOID BETA PROTEIN PRECURSOR IN HEMOSTASIS, RFA
HL-92-05-B
 
THE RFA LABEL (AVAILABLE IN THE 10/88 REVISION OF APPLICATION FORM PHS
398) 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.
 
Application Procedure
 
Send or deliver the completed application and four 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 DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER LETTER OF INTENT.  IT IS
IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND
FOUR 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 March 16, 1992.  An application not
received by this date will be returned to the applicant.
 
Timetable
 
Letter of Intent (optional)              February 15, 1992
Application Receipt Date                 March 16, 1992
Review by the National Heart, Lung,
and Blood Advisory Council and by        September 1992
the National Advisory Council on Aging
Anticipated Award Date                   September 1992
 
INQUIRIES
 
Inquiries regarding this RFA may be directed to the appropriate program
administrator:
 
Dr. Pankaj Ganguly
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5A12
Bethesda, MD  20892
Telephone:  (301) 402-2237
FAX:  (301) 402-1622
 
Dr. Carl D. Banner
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Building 31, Room 5C35
Bethesda, MD  20892
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
 
AUTHORITY AND REGULATIONS
 
The programs of the Division of Blood Diseases and Resources, NHLBI,
and the Neuroscience and Neuropsychology of Aging Program, NIA, are
described in the Catalog of Federal Domestic Assistance Numbers 93.839
and 93.866 respectively.  Awards will be made under the authority of
the Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grants 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.
 
REFERENCES
 
Selkoe, D.J., Deciphering Alzheimer's disease: The amyloid precursor
protein yields new clues. Science 248 (1990) 1058
 
Van Nostrand, W.E. et al., Protease nexin- II (Amyloid beta protein
precursor): A platelet alpha-granule protein. Science 248 (1990) 745
 
Smith, R.P. et al., Platelet Coagulation Factor XIa- inhibitor, a form
of Alzheimer amyloid precursor protein. Science 248 (1990) 1126
 
Van Broeckhoven, C. et al., Amyloid beta protein precursor gene and
hereditary cerebral hemorrhage with amyloidosis (Dutch). Science 248
(1990) 1120
 
Esch, F.S. et al., Cleavage of amyloid beta peptide during constitutive
processing of its precursor. Science 248 (1990) 1122
 
Levy, E. et al., Mutation of the Alzheimer's disease amyloid gene in
hereditary cerebral hemorrhage, Dutch type. Science 248 (1990) 1124
 
Wagner, S.L. et al., Protease nexin-1, an antithrombin with neurite
outgrowth activity, is reduced in Alzheimer's disease.  Proc. Natl.
Acad. Sci. USA 86 (1989) 8284
 
Van Nostrand, W.E. et al., Immunopurification and protease inhibitory
properties of protease nexin 2/amyloid B-protein precursor.  J. Biol.
Chem. 265 (1990) 9591
 
Bush, A.I. et al., The amyloid precursor protein of Alzheimer's disease
is released by human platelets. J. Biol. Chem. 265 (1990) 15977