Monday, June 30, 2025 6/30/2025

Molecular Mechanisms Underlying Endothelial Weibel-Palade Body Biogenesis and Exocytosis

Award Number: K08HL150246
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Molecular Mechanisms Underlying Endothelial Weibel-Palade Body Biogenesis and Exocytosis - Project Summary/Abstract Endothelium plays a vital role in hemostasis and thrombosis. It is essential to maintain blood fluidity, but it also expresses and releases numerous “factors” that regulate blood cell activation and coagulation. Among these, von Willebrand factor (vWF) is an essential plasma hemostatic factor released by the endothelium. Deficiency of mature vWF is the most common bleeding disorder in humans. On the other hand, elevated plasma levels of vWF, or abnormal concentrations of its high-molecular weight multimers, is associated with increased risk of cardiovascular morbidity. As such, understanding of the molecular mechanisms that underlie regulated release of vWF have broad implications in hemostasis and thrombosis. One factor that plays a crucial role in normal vWF exocytosis from endothelial cells is unimpaired biogenesis of its storage granules, the Weibel-Palade bodies (WPBs), which is a highly complex process that remains poorly characterized. We have previously shown that deficiency of biogenesis of lysosome-related organelle complex 2 (BLOC-2) results in impaired vWF exocytosis. Since, BLOC-2, and other related trafficking proteins, are essential for biogenesis of lysosomal-related organelles, a group of specialized granules that includes platelet dense granules and melanosomes, it seems plausible that this protein complex is also required for biogenesis of WPB. We hypothesize that BLOC-2-mediated endosomal trafficking is critical for biogenesis of WPB. We further postulate that the exocyst complex plays an essential role in WPB trafficking by 1) interacting with BLOC-2 in its role in endosomal trafficking 2) and regulating soluble NSF adaptor protein receptor (SNARE)-mediated fusion of WPBs at the plasma membrane. In Aim 1, we will characterize cargo trafficking from the endosomes to the maturing WPBs and the dependence of this pathway on BLOC-2. In Aim 2, we will evaluate the role of the exocyst complex in BLOC-2-dependent endosomal trafficking and characterize the core trafficking machinery involved in this pathway. And, finally, in Aim 3, we will evaluate the regulatory function of the exocyst complex in SNARE-mediated fusion of WPBs at the plasma membrane. The applicant, Dr. Anish Sharda, previously completed clinical and research fellowship in hematology and is currently pursuing a post-doctoral fellowship under the mentorship of Drs. Robert Flaumenhaft and Bruce Furie, who will serve as primary mentor and co-mentor, respectively. The Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center has a distinguished track record of scientific innovation and mentorship, and will provide an excellent environment for the applicant in pursuit of his career goals. The advisory committee of exceptional scientists that Dr. Sharda has established will bring diverse intellectual expertise to his training and scientific growth. Dr. Sharda is well-qualified to execute the proposed experiments and has presented a comprehensive five-year plan to meet his goal of becoming an independent researcher.


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 = $165,024 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Blood Diseases and Resources Research	000	5	5/31/2025	NON-COMPETING CONTINUATION	$165,024
														Subtotal = $165,024

Issue Date FY: 2024 ( Subtotal = $240,624 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Blood Diseases and Resources Research	001	4	5/29/2024	SUPPLEMENT FOR EXPANSION	$75,600
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Blood Diseases and Resources Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$165,024
														Subtotal = $240,624

Issue Date FY: 2023 ( Subtotal = $165,024 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Blood Diseases and Resources Research	004	3	9/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$182,150
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Blood Diseases and Resources Research	001	3	8/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,024
2023	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	8/2/2023	NON-COMPETING CONTINUATION	$0
2023	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	003	2	9/7/2023	NON-COMPETING CONTINUATION	-$165,024
2023	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	002	1	9/7/2023	NEW	-$17,126
														Subtotal = $165,024

Issue Date FY: 2022 ( Subtotal = $165,024 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$165,024
														Subtotal = $165,024

Issue Date FY: 2021 ( Subtotal = $165,024 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	5/19/2021	NEW	$165,024
														Subtotal = $165,024

Grand Total All Awards = $900,720

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Molecular Mechanisms Underlying Endothelial Weibel-Palade Body Biogenesis and Exocytosis

Award Number: K08HL150246

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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