Project Details
Description
Clonal hematopoiesis (CH) arises from somatic mutations such as in JAK2 or TET2 that provide a fitness
advantage to hematopoietic stem cells and outgrowth of clones of blood cells. CH, which increases in frequency
with aging, has emerged as a major independent risk factor for CVD. Studies in Tet2-/- and Jak2VF mouse models
indicate a central role of macrophage inflammasome activation. In collaboration with Drs Tabas and Reilly, we
have shown increased atherosclerosis, defective efferocytosis, increased necrosis and inflammatory myeloid
cell populations in mice expressing Jak2VF in hematopoietic cells. Inhibition of the inflammasome product lL-1β
improved features of plaques stabilization including increased fibrous caps and decreased necrotic cores. The
overall hypothesis is that in several forms of CH including Jak2VF and Tet2, inflammasome activation and IL-1
release from mutant cells promote adverse changes in WT Μφs and stromal cells to induce plaque
destabilization. These studies will synergize with those proposed by Drs Tabas and Zhang that are probing the
mechanisms of defective efferocytosis and thinning of lesional fibrous caps which are key features of
atherosclerotic plaque vulnerability and the major PPG theme. In Aim 1 we will assess the impact of Jak2VF-CH
on bystander cells in lesions focusing on CH Μφ - WT Μφ crosstalk. We will use scRNAseq to evaluate the
hypothesis that IL-1 secretion from Jak2VF Μφs reduces efferocytic Trem2Hi Μφs and increases inflammatory
Μφs. We will employ novel Trem2 stabilizing antibodies to block Trem2 cleavage by IL-1, introduce a transgenic
non-cleavable form of MerTK developed by Dr Tabas and in collaboration with Dr Zhang introduce deficiency
of Pdcd6ip a novel negative regulator of efferocytosis, to see if these potential therapeutic approaches improve
efferocytosis, necrotic core and fibrous cap formation. In Aim 2 we will assess the impact of Jak2VF- and Tet2-/--
CH on Μφ-fibroblast crosstalk. scRNAseq and SMC fate mapping with Dr Reilly shows that IL-1β inhibition in
Jak2VF and Tet2 CH mice increases non-SMC-derived fibroblasts in fibrous caps. We will use fate mapping
studies to assess the hypothesis that fibroblasts are derived from mesenchymal stem cells (MSCs). Aim 3 will
involve translational studies in human carotid plaques. We will collaborate with Dr Maegdefessel, Tabas, Zhang
and the Munich Vascular Biobank to test the hypothesis that CH mutations in TET2, JAK2 and DNMT3A are
associated with increased inflammatory Μφs and decreased Trem2Hi Μφs in carotid plaques with adverse impact
on features of plaque stability. Cells expressing inflammatory or pro-resolving genes will be visualized at single
cell resolution in advanced vs early plaques and in unstable vs stable plaques. These collaborative studies may
reveal novel genes and pathways acting downstream of inflammasome activation in clonal hematopoiesis to
destabilize plaques and point to new and more precisely targeted therapeutic approaches that are less
immunosuppressive than global inhibition of IL-1β or inflammasomes.
Status | Active |
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Effective start/end date | 7/1/24 → 5/31/25 |
ASJC Scopus Subject Areas
- Biotechnology
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