Defining the role of G3BP1 in vascular development

/ABSTRACT Proper blood vessel formation is essential for delivering blood to organs and tissues, crucial for their development and function. However, aberrant blood vessel formation is associated with diverse pathologies including tumor development and fibrotic scarring. Therefore, it is critical to understand the gene regulatory networks underlying blood vessel formation so that these networks can be effectively manipulated during pathological processes as a therapeutic approach. While great strides have been made in recent years to uncover key mechanisms of transcriptional regulation in blood vessel development, relatively little is known regarding post-transcriptional mechanisms that operate during this process. Post-transcriptional regulation serves as the ultimate gatekeeper of protein output within a cell and thus is essential for cellular function during tissue formation. RNA binding proteins (RBPs) bind directly to mRNA to control their stability, decay, and translation into protein, and many RBPs have been correlated with highly angiogenic tumors. Yet, while RBPs represent promising therapeutic targets, virtually nothing is known regarding roles for RBPs in the formation of blood vessels. Evidently, investigating how RBPs regulate blood vessel formation through post-transcriptional regulation will enhance our understanding of the gene regulatory networks underlying blood vessel formation in health and disease. The overall objective of this study is to define the role of the RBP G3BP1 in blood vessel formation. G3BP1 interacts with various components of translational machinery, influencing protein synthesis dynamics in cells. Dysregulation of G3BP1-mediated translation has been implicated in various diseases, including cancer and neurodegenerative disorders, but its role in regulating blood vessel formation remains unknown. I developed a novel g3bp1 loss-of-function mutant zebrafish that exhibit aberrant blood vessel formation. This sets the foundation to tackle the following key questions: (1) what is the role of G3BP1 in blood vessel formation? (2) is G3BP1 regulating blood vessel formation via interactions with translational machinery? To answer these questions, we will utilize high resolution live imaging of developing blood vessels in zebrafish embryos, tissue-specific protein degradation technology in vivo, 2D and 3D primary human cell culture assays, and omics approaches to measure mRNA translation and the G3BP1 protein interactome. This project will reveal G3BP1's role as anew regulator of blood vessel formationand will thus inform how its function contributes to aberrant blood vessel formation in disease contexts, which may ultimately be manipulated for therapeutic gain. Project Number: 1F31HL177906-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Pieter Martino | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10C-B (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17790601