# Oligodendrocyte Progenitors and Hyaluronan-mediated Mechanisms of Human Vascular White Matter Injury > **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $666,934 ## Abstract Project Summary Remyelination failure is the hallmark of microvascular white matter injury (WMI) and commonly causes cognitive impairment and dementia in the elderly. We propose that remyelination failure involves two complementary mechanisms that generate hyaluronic acid fragments (HAf) that disrupt the maturation of oligodendrocyte progenitor cells (OPCs). First, we hypothesize that vascular endothelial cells generate HAf in response to oxidative stress. Second, we hypothesize that vascular injury activates HAf-mediated mechanisms that promote vascular lumen adhesion and trafficking of lymphocytes to cause white matter inflammation and reactive astrocytosis to enhance HA/HAf levels. We will focus on human WMI confirmed by ante-mortem MRI- defined white matter hyperintensities (WMHs). WMHs are the most widely used clinical predictor of risk for vascular cognitive impairment and dementia (VCID). We will define aberrant HAf-mediated actions related to cerebrovascular dysfunction in WMHs. We will build upon two recent advances. First, we will undertake novel vascular physiology studies to define oxidative stress in arterioles isolated from human WMHs. We showed that WM arterioles from VCID cases selectively displayed reduced endothelium-mediated vasodilation that predisposes to WMI (Ann Neurol 83:142-152, 2018). Second, we will define aberrant HAf- mediated mechanisms of myelination failure related to cerebrovascular dysfunction in WMHs. We have defined a signaling pathway activated by cerebral ischemia where a specific bioactive HAf cell autonomously blocks OPC maturation to cause myelination failure (J Clin Invest 128:2025-2041, 2018). We will thus utilize our unique expertise in quantitation and analysis of HA fragments to determine the specific sizes that are linked to myelination failure in WMHs through mechanisms involving the OPC-vascular niche. In aim 1, we will employ a combination of molecular and morphometric approaches to test the hypothesis that remyelination failure in WMHs arises from disrupted HA metabolism that mediates aberrant OPC proliferation and blocks differentiation to myelinating oligodendrocytes. We will isolate vascular endothelial cell-derived HAf from WMHs and determine its actions on OPC proliferation and differentiation. In aim 2, we will utilize a combination of molecular, biochemical and histochemical approaches to test the hypothesis that WM vascular dysfunction and oxidative/nitrosative stress are linked to altered HA synthesis, catabolism and signaling in WMHs. In aim 3, we will employ novel murine and human in vitro models to test the hypothesis that dysfunction of WM arterioles promotes inflammatory mechanisms of myelination failure mediated by vascular lumen adhesion and trafficking of lymphocytes into WMHs. Our over-riding objective is to provide a mechanistic molecular explanation for the distinct OPC-vascular processes that render aging human white matter particularly susceptible to microvascular WMI in ord... ## Key facts - **NIH application ID:** 10875693 - **Project number:** 4R01AG065406-02 - **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY - **Principal Investigator:** Stephen Arthur Back - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $666,934 - **Award type:** 4N - **Project period:** 2020-09-15 → 2025-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10875693 ## Citation > US National Institutes of Health, RePORTER application 10875693, Oligodendrocyte Progenitors and Hyaluronan-mediated Mechanisms of Human Vascular White Matter Injury (4R01AG065406-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10875693. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*