# The role of pericytes in white matter disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $722,149

## Abstract

In response to the RFA-NS-16-021 to address some of the gaps in our knowledge of the biologic mechanisms
of the commonly occurring cerebrovascular disease and age-related white matter (WM) disease at the
molecular, cellular and brain circuit level, we propose to study the role of pericytes in WM disease using new
pericyte-specific animal models and advanced molecular, cellular and neuroimaging methods, and circuit level
analysis. Up to 45% of all dementias worldwide are estimated to be wholly or partly due to age-related small
vessel disease (SVD) of the brain. Pericytes are vascular mural cells embedded in the wall of small blood
vessels such as capillaries, pre-capillary arterioles, and post-capillary venules. In the brain, they control key
neurovascular functions such as blood-brain barrier (BBB) integrity and cerebral blood flow (CBF). Pericyte
degeneration leads to BBB breakdown and impaired hemodynamic responses, and is found in neurologic
disorders exhibiting SVD, WM disease and cognitive impairment such as Alzheimer's, stroke and CADASIL -
the most common genetic cause of ischemic SVD and VCID; yet, the role of pericytes in the pathophysiology
of SVD and WM disease is largely not known. Based on our pilot data obtained in pericyte-deficient platelet-
derived growth factor receptor-β (PdgfrβF7/F7) mice and published studies in TgNotch3R169C mice expressing
Notch3 CADASIL mutant in vascular smooth muscle cells and pericytes, we hypothesize that WM pericyte loss
leads to BBB breakdown and CBF reductions causing loss of oligodendrocytes, demyelination, axon damage,
disrupted connectivity and disintegration of CNS circuits, which leads to functional deficits and neuron loss.
Since currently available pericyte-deficient Pdgfb/Pdgfrβ lines and TgNotch3R169C mice are not pericyte specific,
to test our hypothesis we have generated new pericyte-specific lines such as Pdgfrβ-Flp; Cspg4-FSF-CreER;
iDTR mice with inducible pericyte ablation, and will develop a new mouse line with inducible expression of
Notch3R169C mutation only in pericytes. We will use i) cutting-edge longitudinal dynamic contrast-enhanced
magnetic resonance imaging (MRI) of regional BBB integrity, dynamic susceptibility contrast MRI of CBF,
diffusion tensor imaging (DTI) and DTI-based tractography for structural/connectivity changes, and tract-tracing
based connectomics for CNS circuit level analysis; ii) behavior tests; and iii) immunohistology,
neuropathology, flow cytometry, and electron microscopy tissue analyses. We will determine the effects of
global inducible pericyte ablation (20-70%) (AIM 1), focal inducible pericyte loss in the anterior cingulum of the
corticolimbic ciruit (AIM 2) and pericyte-specific inducible Notch3R169C expression (AIM 3) on BBB integrity,
CBF reductions, WM integrity, disruption of CNS circuits and functional deficits (behavior). We expect that the
proposed studies will contribute towards better understanding of the mechanistic basis of WM disease i...

## Key facts

- **NIH application ID:** 9996809
- **Project number:** 5R01NS100459-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Berislav V Zlokovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $722,149
- **Award type:** 5
- **Project period:** 2016-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996809

## Citation

> US National Institutes of Health, RePORTER application 9996809, The role of pericytes in white matter disease (5R01NS100459-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996809. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*