# Aging and clonality in atherosclerosis

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $209,375

## Abstract

PROJECT SUMMARY / ABSTRACT
 Ischemic heart disease and stroke primarily result from atherosclerosis and are leading causes of
mortality in the elderly. However, the reasons why the elderly are particularly susceptible to atherosclerosis
and related diseases are incompletely understood. A key factor for this knowledge gap is that the vast majority
of rodent studies of atherosclerosis utilize young mice. Our overall goal is to generate seminal insights into
atherogenesis and thereby, devise novel strategies to reduce the heavy burden of cardiovascular diseases in
the elderly. The proposed studies result from a synergistic collaboration between two investigators with
complimentary expertise: Daniel Greif, M.D. (smooth muscle cell [SMC] biology, lineage and clonal analysis
and cardiovascular disease) and Carlos Fernández-Hernando, Ph.D. (lipid metabolism, vascular biology and
inflammation and atherosclerosis models). Recent studies from our laboratories and other groups suggest that
rare progenitors expressing SMC markers are recruited into atherosclerotic plaques and clonally expand.
Indeed, our recent joint paper demonstrates that a single pre-existing SMC gives rise to the majority of all the
cells in an advanced atherosclerotic plaque and that bone marrow-derived cells (presumably macrophages)
regulate the recruitment and clonal expansion of SMC progenitors (Nature Communications, 2018, in press).
We also demonstrate that in contrast to SMC progenitors, multiple myeloid cells are recruited into
atherosclerotic plaques. A strong correlation between clonal hematopoiesis and atherosclerotic cardiovascular
disease has recently been identified; however, it is not known whether there is clonal expansion of
macrophages within plaques and if so, the impact of such clonal expansion. Similarly, it remains to be
determined how aging influences SMC clonality and the importance of clonal hematopoiesis in regulating
plaque progression. We suggest that aging has deleterious effects on the recruitment of pre-existing
myeloid or SMC marker+ progenitors into atherosclerotic plaques and their clonal expansion. Our
proposed studies utilize young and old transgenic mice carrying a multi-color Cre reporter and subjected to a
state-of-the-art model of atherosclerosis - single injection with recombinant, replication-deficient AAV vector
encoding a gain-of-function Pcsk9 transgene to reduce LDL receptor levels, followed by Western diet – and
also utilize isolated SMCs, bone marrow-derived cells and plaque cells. Our investigations have two specific
aims: 1) determine effects of aging on atherosclerotic plaque burden and content and on the architecture and
gene expression of clones of myeloid-derived plaque cells; and 2) elucidate effects of aging on the fate and on
the architecture and gene expression of clones of SMC-derived plaque cells. The experiments delineated in
this R21 proposal will yield key insights into atherogenesis and will provide the groundwork for a futu...

## Key facts

- **NIH application ID:** 9849714
- **Project number:** 5R21AG062202-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carlos Fernandez Hernando
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849714

## Citation

> US National Institutes of Health, RePORTER application 9849714, Aging and clonality in atherosclerosis (5R21AG062202-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849714. Licensed CC0.

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