EXPLORING BRAIN PERIVASCULAR FIBROBLASTS IN HEALTH AND CEREBRAL AMYLOID ANGIOPATHY - PROJECT SUMMARY MAINTA…

Assistance award details

Assistance award identifier

ASST_NON_R00AG080034_075

FAIN

R00AG080034

Recipient

THE REGENTS OF THE UNIVERSITY OF COLORADO

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$493,293

Period

Aug 1, 2023 – Jan 31, 2028

Fiscal year

2025

Place of performance state

CO

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

EXPLORING BRAIN PERIVASCULAR FIBROBLASTS IN HEALTH AND CEREBRAL AMYLOID ANGIOPATHY - PROJECT SUMMARY MAINTAINING A STABLE BRAIN VASCULAR NETWORK IS CRUCIAL FOR ENSURING OVERALL BRAIN HEALTH THROUGHOUT LIFE. PERIVASCULAR CELLS, LIKE PERICYTES AND SMOOTH MUSCLE CELLS, ARE CRUCIAL TO MAINTAIN THE INTEGRITY OF THE BRAIN VASCULATURE. LOSS OF PERICYTES AND SMOOTH MUSCLE CELLS ARE NOTED IN ALZHEIMER’S DISEASE (AD) AND AFFECTS VASCULAR INTEGRITY, ULTIMATELY CONTRIBUTING TO DISEASE PATHOLOGY. PERIVASCULAR FIBROBLASTS (PVFS) ARE ANOTHER CELL POPULATION ALONG THE BRAIN VASCULATURE, HOWEVER THEIR ROLE IS LARGELY UNKNOWN. PVFS EXPRESS NUMEROUS EXTRACELLULAR MATRIX PROTEINS THAT ARE UNIQUELY FOUND ON ARTERIOLES AND VENULES BUT NOT CAPILLARIES. MY PRELIMINARY INVESTIGATIONS INDICATE THAT PVFS MAINTAIN VESSEL STRUCTURAL STABILITY, PARTICULARLY ALONG ARTERIOLES, IN THE HEALTHY BRAIN. FURTHER, I FIND THAT ARTERIOLES ARE MORE TORTUOUS IN A MOUSE MODEL OF CEREBRAL AMYLOID ANGIOPATHY (CAA), AND THIS IS ASSOCIATED WITH A SIGNIFICANT REDUCTION IN PVFS. CAA IS A SMALL VESSEL DISEASE CHARACTERIZED BY THE ACCUMULATION OF AMYLOID- ON VESSELS COMMONLY OBSERVED IN AD. ARTERIOLES AND THEIR IMMEDIATE OFF-SHOOTS ARE IMPORTANT MAJOR REGULATORS OF BLOOD FLOW INTO THE BRAIN. IN DOING SO, THEY UNDERGO EXTENSIVE DILATION AND CONSTRICTION EVENTS WHICH IS LIKELY SUPPORTED IN PART BY EXTRACELLULAR MATRIX PROTEINS EXPRESSED BY PVFS. THE GOAL OF THIS PROPOSAL IS TO DETERMINE IF PVFS REGULATE ARTERIOLE STRUCTURE AND DYNAMICS IN THE HEALTHY BRAIN. FURTHER, MY GOAL IS TO UNDERSTAND IF CAA CONTRIBUTES TO PVF LOSS, ALTERING ARTERIOLE STRUCTURE AND DYNAMICS BY AFFECTING THE EXPRESSION OF EXTRACELLULAR MATRIX PROTEINS, ULTIMATELY EXACERBATING CAA. UNDERSTANDING THESE IMPORTANT ASPECTS OF THE BRAIN VASCULATURE COULD ULTIMATELY PROVIDE A POTENTIAL FOR DEVELOPING THERAPEUTICS AIMED AT LIMITING AD PATHOLOGY AND IMPROVE VASCULAR FUNCTION. THE TRAINING I WILL RECEIVE UNDER THE GUIDANCE OF DR. ANDY SHIH, WHO IS AN