[K99] Targeting Angiocrine Signaling in Vascular Repair and Ischemic Stroke Recovery
Ente: National Heart Lung and Blood Institute
Scadenza: 2028-05-31
Importo max: 139.822 EUR
Paese: US
Descrizione
Abstract
Endothelial cells (EC) are central regulators of vascular homeostasis, angiogenesis, and barrier integrity. EC
dysfunction, injury, and inadequate angiogenesis drive cerebrovascular and cardiovascular diseases, including
ischemic stroke and atherosclerosis. Restoring endothelial function remains a critical unmet need and a
promising therapeutic avenue. This project will uncover a previously unrecognized role of endothelial-specific
epsins in regulating CXCR4-mediated angiocrine signaling and develop a targeted nanoparticle therapy to
inhibit endothelial epsins and enhance vascularization of the brain following experimental induction of stroke.
During the K99 phase, I will investigate how epsins, which act as endocytic adaptor proteins, regulate CXCR4
signaling, a key pathway governing angiogenesis and vascular repair, and define the molecular mechanisms
by which endothelial epsins control CXCR4 activity in stroke models. I have begun mechanistic studies using
biochemical assays to characterize epsin–CXCR4 interactions and their role in CXCR4 trafficking and
degradation in primary brain endothelial cells, and I have generated inducible endothelial cell–specific epsin
knockout mice that show enhanced angiogenesis and improved stroke recovery. In the K99 and R00 phases, I
will further evaluate how targeted inhibition of endothelial epsins affects angiogenesis and stroke outcomes in
vivo, engineer an EC-specific nanoparticle system to selectively inhibit endothelial epsins, and integrate
scRNA-seq, scATAC-seq, and MERSCOPE spatial transcriptomics to identify chromatin-level regulation,
spatial relationship between individual cells and expression of downstream targets of CXCR4 signaling. The
innovative findings from this proposal have the potential to establish a new therapeutic paradigm for ischemic
stroke and other cardiovascular diseases in which vascularization is a crucial therapeutic strategy for recovery.
My extensive training in designing and analyzing computational and experimental approaches, including multi-
omics data analysis, positions me well to successfully execute the proposed studies. The project will be
supervised by an interdisciplinary mentorship team, including Dr. Hong Chen (vascular biology and
experimental expertise) and Dr. Kaifu Chen (bioinformatics and computational genomics), along with a strong
advisory committee with expertise in vascular endothelial biology, nanoparticle design, angiogenesis,
molecular cell biology, and cancer biology. My training plan also includes professional development in scientific
writing, communication, and mentoring. The outstanding research environment at Boston Children's Hospital
and Harvard Medical School will further strengthen the successful completion of this proposal. Completion of
the K99 training period will prepare me for a smooth transition into the R00 phase and for establishing an
independent research program in translational vascular biology and genomic medicine.
Istituzione: BOSTON CHILDREN'S HOSPITAL
PI: Kulandaisamy Arulsamy
Progetto: 1K99HL183664-01A1
Settori: National Heart Lung and Blood Institute
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