# Signal Transduction by alphavbeta8 Integrin

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $396,000

## Abstract

Abstract
The brain is the most vascularized organ in the mammalian body, with its complex network of
blood vessels interacting with neurons and glia in multicellular complexes termed neurovascular
units. Growth factors and extracellular matrix (ECM) proteins coordinately regulate adhesion
and signaling between neural cells and vascular cells to promote normal brain development and
physiology. These events are deregulated in many brain pathologies, including developmental
disorders such as germinal matrix hemorrhage and age-related neurocognitive deficits such as
Vascular Dementia. We understand surprisingly little about mechanisms that regulate normal
neural-vascular cell contact and communication or how these events go awry during disease
pathogenesis. Here, we will analyze roles for ECM proteins and their integrin receptors in
neurovascular biology and disease. Integrins are a-b heterodimeric proteins that link ECM
ligands to the cytoskeleton and control intracellular signaling cascades. While a great deal is
known about adhesion and signaling functions for most integrins, the pathways controlled by
integrin avb8, which was discovered more than 25 years ago, remain largely unexplored. avb8
is expressed in glial cells of the central nervous system (CNS) and plays critical roles in
regulating vascular endothelial cell behaviors via activation of ECM-bound latent-transforming
growth factor b (TGFb) protein ligands. In this renewal project, we will develop genetically
engineered mouse models and primary cell culture systems to analyze avb8 integrin-mediated
adhesion and signaling pathways in neurovascular unit pathophysiology. First, we will
characterize a newly developed knock-in mouse model that enables dissection of avb8 integrin
extracellular adhesion from intracellular signaling in neural-vascular cell contact and
communication. In particular, we will study integrin-dependent blood vessel morphogenesis and
endothelial barrier formation in the brain and retina. Second, we will determine functions for the
b8 cytoplasmic domain in regulating integrin inside-out activation and ECM affinity/avidity using
biochemical assays and primary cell culture models. Third, we will explore paracrine signaling
between avb8 integrin in perivascular glial cells and TGFb receptors in endothelial cells. A
particular focus will be placed on integrin-dependent regulation of the docosahexaenoic (DHA)
transporter Mfsd2a in CNS endothelial cells. Fourth, we will explore links between defective
DHA metabolism and BBB dysfunction in the progressive neurodegenerative pathologies that
develop in integrin mutant mice. In summary, experiments in this project will reveal new and
important mechanisms underlying integrin control of neurovascular development and
physiology. The mutant mouse models may also provide valuable insights into pathways
involved in the pathogenesis of vascular-related neurological diseases.

## Key facts

- **NIH application ID:** 10064016
- **Project number:** 5R01NS087635-07
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Joseph H McCarty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,000
- **Award type:** 5
- **Project period:** 2014-08-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064016

## Citation

> US National Institutes of Health, RePORTER application 10064016, Signal Transduction by alphavbeta8 Integrin (5R01NS087635-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10064016. Licensed CC0.

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