# REGULATION OF HUMAN MEGAKARYOCYTOPOIESIS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 1993 · $255,299

## Abstract

The long term goal of this project will be to generate a comprehensive
understanding of the subcellular and molecular events which regulate normal
human megakaryocytopoiesis.  Our specific aims will be to 1:  Determine the
role of arc family tyrosine kinases, and G alpha proteins in transducing
growth factor mediated signals from cytoplasm to nucleus:  We hypothesize
that tyrosine kinases and G proteins may play an important role in
transducing growth factor initiated signals.  We will test this hypothesis
by determining megakaryocyte responsiveness to known growth factors after
blocking de novo synthesis of these proteins with antisense
oligodeoxynucleotides, or microinjecting antibodies to G proteins into
megakaryocytes; 2:  Determine the temporal sequence of expression and
functional significance of selected cell cycle and growth regulated genes
expressed during normal human megakaryocytopoiesis:  Using in situ
hybridization, the polymerase chain reaction, and antisense
oligodeoxynucleotides for blockade of specific gene function we will begin
to gather these data for genes of particular importance in megakaryocyte
development; 3) Determine the molecular mechanisms which regulate
megakaryocyte polyploidization:  We hypothesize that megakaryocyte nuclear
endoreduplication is the result of events which occur primarily during the
G2/M interphase of the cell cycle.  We will test this hypothesis by
selectively perturbing events which occur during this phase of the cell
cycle and determining if increased megakaryocyte polyploidy in response to
defined stimuli (e.g. IL-3, IL-6) still occurs.  We will also construct
cDNA libraries from quiescent and growth factor stimulated megakarocytes to
identify genes that might be unique, differentially expressed, or
conversely not expressed at all, in stimulated cells; 4) Determine the
mechanism whereby platelet factor 4 (PF4) inhibits megakaryocytopoiesis:
We hypothesize that megakaryocytopoiesis is inhibited by PF4 through
several possible mechanisms including:  i) induction of c-myc and/or c-myb
protooncogenes, ii) induction of transcription factors which may play a
role in maturation and/or polyploidization (e.g. c-jun, c-fos, or other TPA
responsive elements), or iii) impairment of response to growth factors.  We
will test these alternative hypotheses using the approaches described
above.  The availability of recombinant hematopoietic growth factors,
improved culture systems, and molecular "micromethodologies" now make these
difficult and important questions amenable to study.  Since megakaryocyte
related thrombocytopenia remains a significant problem after cancer
chemotherapy, bone marrow transplantation, and in some patients with
acquired immunodeficiency syndrome (AIDS) this is a clinically important
area of investigation.

## Key facts

- **NIH application ID:** 3174515
- **Project number:** 5R01CA036896-10
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **SAM.gov UEI:** GM1XX56LEP58
- **Principal Investigator:** Alan M Gewirtz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $255,299
- **Award type:** 5
- **Project period:** 1984-03-01 → 1996-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174515

## Citation

> US National Institutes of Health, RePORTER application 3174515, REGULATION OF HUMAN MEGAKARYOCYTOPOIESIS (5R01CA036896-10). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174515. Licensed CC0.

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