# Molecular Mechanisms Underlying Endothelial Weibel-Palade Body Biogenesis and Exocytosis

> **NIH NIH K08** · YALE UNIVERSITY · 2024 · $165,024

## Abstract

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...

## Key facts

- **NIH application ID:** 10898871
- **Project number:** 5K08HL150246-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Anish Vaibhav Sharda
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $165,024
- **Award type:** 5
- **Project period:** 2023-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898871

## Citation

> US National Institutes of Health, RePORTER application 10898871, Molecular Mechanisms Underlying Endothelial Weibel-Palade Body Biogenesis and Exocytosis (5K08HL150246-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898871. Licensed CC0.

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