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Mechanisms of Delta-like 4 Endocytosis and Notch Activation During Blood Vessel Development

Award Number: R15HL156106
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Mechanisms of Delta-like 4 Endocytosis and Notch Activation During Blood Vessel Development - SUMMARY Endothelial cells (ECs) are the cell type responsible for the bulk of embryonic blood vessel formation, eventually leading to an estimated 100,000 miles of vasculature by adulthood. During development, new blood vessels emerge from pre-existing vasculature, a process termed angiogenesis. Notch signaling is fundamental to angiogenesis and adult blood vessel homeostasis. In the absence of Notch, blood vessels demonstrate a chronic sprouting phenotype marked by unchecked proliferation and overgrowth; this evidence and others overwhelmingly show Notch is required for blood vessel maturation and stability. When ligand-bound, the Notch intracellular domain is cleaved and translocates to the nucleus, acting as a transcription factor. Delta-like ligand 4 (DLL4) is a potent Notch ligand that binds to the extracellular domain of Notch. To elicit Notch activation the ectodomain of Notch requires a pulling force by DLL4 to expose a S2 cleavage site. Once exposed, the Notch extracellular domain is cleaved, allowing for release of the Notch intracellular domain (NICD) stimulating signaling activation. Very little is known about the post-transcriptional regulation of DLL4, and even less is understood about the mechanisms by which DLL4 exerts a sustained pulling force to activate Notch-mediated lateral inhibition. Our preliminary data describes, for the first time, how DLL4 endocytosis and anchoring to the actin cytoskeleton generates the mechanical force required to expose the S2 site of Notch. Specifically, this proposal will focus on two largely uncharacterized proteins we believe are central to force- generating DLL4 endocytosis, Eps15 homology domain binding protein 1 (EHBP1) and EH domain containing protein 2 (EHD2). Our broad hypothesis is that EHBP1 anchors EHD2 to f-actin filaments, aiding in the transendocytosis of DLL4 bound to Notch. In Aim1 we will detail how both EHBP1 and EHD2 work in combination to facilitate DLL4 endocytosis, and in doing so, mediate Notch signaling. In Aim2, we will comprehensively demonstrate that EHBP1 and EDH2 works in combination to regulate DLL4 endocytosis and downstream Notch activity during zebrafish blood vessel morphogenesis using live-imaging and CRISPR- based mutant generation. Overall, this proposal will answer several critically important questions pertaining to blood vessel development as well as provide a powerful training opportunity for undergraduate scholars.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$15,754 )
2025	2021	UNIVERSITY OF DENVER	2199 S UNIVERSITY BLVD RM 222	DENVER	CO	80210	DENVER	USA	Cardiovascular Diseases Research	000	1	11/12/2024	NEW	-$15,754
														Subtotal = -$15,754

Issue Date FY: 2021 ( Subtotal = $439,024 )
2021	2021	COLORADO SEMINARY	2199 S UNIVERSITY BLVD	DENVER	CO	80210	DENVER	USA	Cardiovascular Diseases Research	000	1	5/27/2021	NEW	$439,024
														Subtotal = $439,024

Grand Total All Awards = $423,270

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Mechanisms of Delta-like 4 Endocytosis and Notch Activation During Blood Vessel Development

Award Number: R15HL156106

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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