# Basic Investigation and Translational Applications Concerning the Cell and Molecular Biology of Blood and Vascular Cells

> **NIH NIH R35** · VERSITI BLOOD HEALTH, INC. · 2020 · $986,569

## Abstract

Studies proposed in this application encompass and extend long-standing interests of the Principal
Investigator in the cell and molecular biology of blood and vascular cells. The proposed Program is comprised
of two ambitious, impactful projects designed to fill important conceptual gaps in their respective fields, and that
have long been judged to be of interest and relevance to the overall mission of the NHLBI; namely (1) The role
of PECAM-1 in vascular cell function, and (2) The pathophysiology of neonatal alloimmune thrombocytopenia
(NAIT). PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor that functions in circulating
blood cells to limit the rate and extent of cellular activation. PECAM-1 is also the most highly-expressed
component of the endothelial cell-cell junction, where it functions as a homophilic adhesive stress-response
protein to maintain endothelial cell junctional integrity and speed restoration of the vascular permeability barrier
following inflammatory or thrombotic challenge. We will exploit our recent determination of the three-dimensional
structure of the PECAM-1 homophilic binding domain, our development of innovative PECAM-1-targeted tools
and animal models, and our discovery that PECAM-1 is subject to conformational affinity modulation to examine
the potential for PECAM-1 to serve as a novel therapeutic target for a wide range of vascular permeability
disorders, including sepsis-induced vascular leakage and ischemia-reperfusion injury. This Program will also
focus on developing new tools, models and treatments for NAIT – a rare, but catastrophic, clinically important
bleeding disorder caused by maternal antibodies generated in response to paternally-inherited antigens present
on fetal platelets that re-cross the placenta and bind to fetal and/or neonatal platelets, resulting in
thrombocytopenia often serious enough to require transfusion, and in the most severe cases causing intracranial
hemorrhage and intrauterine death. Despite advances in treatment, NAIT remains the leading cause of
intracranial hemorrhage in full-term infants, often leading to lifelong disability. We propose to combine recent
transformative advances in CRISPR gene editing technology with the ability to generate megakaryocyte
progenitor cells, megakaryocytes, and platelets from induced pluripotent stem cells to establish a transformative
diagnostic platform designed to narrow the existing “diagnostic gap” to improve treatment and care of NAIT -
namely the creation of platelet alloantigen-specific cell lines capable of long-term self-renewal, cryopreservation,
and distribution; thereby providing a potentially inexhaustible source of iPS-derived platelets for diagnostic,
investigative, (and potentially future therapeutic) use. CRISPR technology has also allowed us to develop a novel
humanized mouse model of NAIT that will allow us to resolve a series of outstanding issues in platelet
alloimmunity. Taken together, this research p...

## Key facts

- **NIH application ID:** 9878914
- **Project number:** 5R35HL139937-03
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Peter J Newman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $986,569
- **Award type:** 5
- **Project period:** 2018-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878914

## Citation

> US National Institutes of Health, RePORTER application 9878914, Basic Investigation and Translational Applications Concerning the Cell and Molecular Biology of Blood and Vascular Cells (5R35HL139937-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9878914. Licensed CC0.

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