Department of Physiology and Neurobiology

University of Connecticut

Storrs, CT

BASIC RESEARCH PROJECT

Modulation of retinal vascularization by endothelial cell genetic reprogramming

Research Interests

Abnormal formation of new blood vessels is the fundamental cause of catastrophic vision loss during ocular neovascularization, stressing the urgent need for new treatments. Current therapies aim to destroy aberrant vascularization by neutralizing Vascular Endothelial Growth Factor-A (VEGF). Yet, these approaches do not address the causes that underlie vascular pathology, such as hypoxia and inflammation. We therefore aim to identify VEGF-independent signaling pathways, that could promote vascular repair and regeneration of the diseased eye. One pathway that holds promise is Transforming Growth Factor (TGF) β and its receptor (R) 1 (TGFBR1), which are specifically required during developmental vascular growth in the neuroretina. Dr. Zarkada hypothesizes that activation of TGFβ/TGFBR1 signaling could force sprouting endothelial cells to acquire the abilities to form a leak-proof and properly patterned vasculature in the neuroretina. She will therefore generate a new genetic mouse model to test this hypothesis during developmental retinal vascularization.

Plans for 2024

This project will provide proof or principle that reprogramming endothelial cell identity could be a successful alternative approach to treat neovascular eye disease. The
project will yield key insights into TGFβ biology during retinal vascularization (this proposal), and during preclinical models of ocular neovascular disease (future plans).

Specific Aims:
In Aim 1 – To design, validate, and generate a genetically engineered mouse model to
overexpress TGFBR1 in endothelial cells in a spatial and temporal-controlled manner.

In Aim 2 – To perform in vivo validation of endothelial-specific overexpression of TGFBR1 and analyze the effects of increased TGFβ/TGFBR1 signaling during developmental retinal angiogenesis.