# Evaluating the Mechanism for Hyperhomocysteinemia Induced Vascular Pathology

> **NIH NIH F31** · UNIVERSITY OF KENTUCKY · 2021 · $38,968

## Abstract

PROJECT SUMMARY
 Vascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of
dementia along with Alzheimer’s disease (AD) and approximately 60% of patients with AD also present with
VCID. Despite its common clinical manifestation, the mechanism underlying VCID remains elusive. Based on
extensive data analysis in humans and animal models, a specific family of proteinases that degrade essential
components of the blood brain barrier (BBB), in particular matrix metalloproteinase 9 (MMP9), were identified
as being strongly associated with progression of VCID. MMP9 degrades tight junctions between endothelial
cells and the anchoring proteins located at the astrocytic end feet. I hypothesize that upregulation of MMP9
results in the dissociation of perivascular astrocytes from their vessels, leading to BBB dysfunction and the
progression toward VCID.
 To test this hypothesis, I propose in vivo studies in a hyperhomocysteinemia (HHCy) mouse model of
VCID in both wild type (WT) and MMP9 null mice (Aim 1) alongside astrocyte-specific, in vitro studies using
WT and MMP9 null primary astrocytes (Aim 2). We have shown that induction of HHCy in WT mice is
associated with microhemorrhages, reduced blood flow, neuroinflammation and cognitive impairment indicating
its relevance in recapitulating the clinical manifestations of VCID. Preliminary data shows our HHCy model of
VCID induces decreased contact of astrocytic end-feet with the vasculature. Aim 1 will assess the role of
MMP9 in the progression of VCID pathology in response to HHCy in vivo by examining changes in
neurovascular coupling and associations between astrocyte end feet and the cerebrovasculature using two-
photon imaging. Aim 2 will investigate the astrocyte-specific role of MMP9 in disruption of the BBB. Using
primary cells obtained from both WT and MMP9 null mice, I will use trans-endothelial electrical resistance
measurements (TEER) in an astrocyte/endothelial cell co-culture model to assess BBB integrity in response to
HHCy. By elucidating the cell specificity and mechanism of MMP9 mediated vascular pathology we can
systematically target the various stages of disease progression and ultimately prevent the progression of VCID.
 Through completion of this project, I will receive training in both in vitro and in vivo models of VCID,
which, coupled with my previous training in human subjects will expose me to all aspects of translational
research. Additionally, I will regularly present data at both international and national meetings, I will be involved
in experimental design and ethics workshops and will gain experience mentoring junior scientists. These
experiences, coupled with the mentorship of the renowned scientists on my committee, will ensure that I am
well prepared to successfully secure a post-doctoral fellowship in the field of neurodegeneration.

## Key facts

- **NIH application ID:** 10312905
- **Project number:** 1F31AG074530-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Alexandria Early
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,968
- **Award type:** 1
- **Project period:** 2021-09-27 → 2024-09-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312905

## Citation

> US National Institutes of Health, RePORTER application 10312905, Evaluating the Mechanism for Hyperhomocysteinemia Induced Vascular Pathology (1F31AG074530-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312905. Licensed CC0.

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