Project Details
Description
Cardiovascular diseases are both common and deadly. For example, peripheral artery disease affects more
than 10M Americans resulting in more than 150,000 limb amputations each year in the U.S. In addition, more
than 300,000 patients have coronary artery bypass grafting (surgical revascularization). Current medical
therapies for vascular disease include limb amputation and vascular bypass grafting--these therapeutic
interventions have significant limitations. These diseases are chronic, debilitating, lethal and they warrant new
and novel therapies. Previous studies have demonstrated the essential role for pioneer factors that modulate
chromatin accessibility and thereby impact the binding of early transcriptional regulators for lineage
specification. We have recently demonstrated that ETV2 is an essential pioneer factor for endothelial, vascular
and blood lineages. We have used global and conditional gene disruption strategies, fate-mapping, gene
editing, single cell RNA-seq, ATAC-seq and ChIP-seq assays to provide supportive data for this application. In
addition, we defined an important ETV2-miR130a-PDGFRa cascade that governs endothelial development.
Furthermore, our recent publications and our preliminary data support the overall hypothesis that
ETV2 is a pioneer factor that regulates the specification of the endothelial lineage. In these proposed
studies, we will use a number of unique genetic models that we have engineered and we take an innovative
strategy to define the mechanisms whereby ETV2 functions as a pioneer factor to regulate cardiovascular
regeneration. To examine our hypotheses, we will address the following specific aims: Specific Aim #1:
Specific Aim #1: To further define the mechanisms whereby ETV2 functions as a pioneer factor during
embryogenesis and reprogramming to the endothelial lineage; Specific Aim #2: To define the role of
chromatin modifying factors and ETV2 during embryogenesis and reprogramming to the endothelial
lineage and Specific Aim #3: To examine the factors that promote ETV2 mediated reprogramming of
the endothelial lineage in vitro and in vivo. These aims will utilize our recently engineered genetic mouse
models, ATAC-seq, MNase-seq, ChIP-seq, inducible mouse model, cardiac injury model in the adult mouse,
novel and bioinformatics algorithms to comprehensively define the mechanisms whereby ETV2 functions as a
pioneer factor and will serve as prelude for therapeutic initiatives to engineer and promote regeneration of the
cardiovascular lineages. Given the tremendous morbidity and mortality of cardiovascular disease in our
society, the potential impact of this proposal is significant.
Status | Active |
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Effective start/end date | 5/20/23 → 4/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $697,432.00
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