# Studies of Physiologic and Pathologic Platelet Plug Formation

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $2,423,078

## Abstract

PROGRAM INTRODUCTION SUMMARY:
This is the re-submission of a new Program Project (HL146373-01) that we have re-named
“Studies of Physiologic and Pathologic Platelet Plug Formation” to more accurately reflect the
topics the Program Project addresses. In addition to forming hemostatic plugs at sites of
vascular injury, platelets make important contributions to processes such as inflammation,
tissue regeneration, host defense, angiogenesis, lymphatic development, and tumor metastasis.
Pathologic platelet thrombi are also responsible for much of the morbidity and mortality of
arterial vascular disease. There remain large gaps in our understanding of physiologic and
pathologic platelet function. Building upon our collective scientific accomplishments, we address
these gaps using the cell-biologic, structural-biologic, and computational-biologic methods we
have developed. The Program Project we propose consists of four projects and one
administrative core unit. All of the projects are based at the Perelman School of Medicine of the
University of Pennsylvania. Three projects are based in the Hematology-Oncology Division of
the Department of Medicine; the fourth is based in the Division of Hematology of the
Department of Pediatrics at The Children's Hospital of Philadelphia. Project 1, re-named “Novel
Roles for Phosphoinositide Signaling in α-Granule Biogenesis”, is based on the hypotheses that
phosphoinositide synthesis is an essential step in the loading of α-granules with components
synthesized in the Golgi and that megakaryocyte phosphoinositides play a previously
unrecognized role in the development of congenital megakaryocyte disorders. The objectives of
Project 2, entitled “Platelet Integrin Structure and Function”, are to use novel computational and
experimental techniques to compare the behavior of αIIbβ3 with that of the other integrins and
to identify and quantify the protein-protein interactions responsible for αIIbβ3-mediated fibrin clot
contraction. Project 3 is entitled “A Systems Approach to Hemostasis and Thrombosis“. The
goals of the studies proposed in this Project are to extend past analyses of platelet thrombus
formation and structure from the microvasculature to the macrovasculature, from mice to
humans, and from hemostasis to thrombosis. Project 4, entitled “Platelet Factor 4 and Heparin
in NETosis and Sepsis”, will test the hypothesis that NETs, neutrophil extracellular traps
composed of chromatin released by neutrophils, require partial digestion and release of DNA
and histones to be toxic during sepsis. Because infused platelet factor 4, as well as the
monoclonal antibody KKO that binds to the complex of platelet factor 4 and heparin, block DNA
digestion, both will be protective in sepsis. The four projects are supported by a single core unit
that provides for the common administrative needs of the Program.

## Key facts

- **NIH application ID:** 9855723
- **Project number:** 1P01HL146373-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joel S. Bennett
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,423,078
- **Award type:** 1
- **Project period:** 2020-05-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855723

## Citation

> US National Institutes of Health, RePORTER application 9855723, Studies of Physiologic and Pathologic Platelet Plug Formation (1P01HL146373-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9855723. Licensed CC0.

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