Uncontrolled capillary formation is a major contributor to numerous diseases including cancer, diabetic retinopathy, and wet macular degeneration-all exhibiting a high incidence in the general population and having limited long term treatment options. Recent clinical trials using the drug Bevacizumab (Avastin), which inhibits blood vessel formation, demonstrated one of the largest improvements in survival ever reported in a randomized study of patients with metastatic colorectal cancer. While many drugs targeting blood vessel formation in diseased tissue exhibit limited side effects and have been proven to delay disease progression, there still exists no cure for these diseases, and identification of novel vascular targets could lead to more effective therapeutics. The long term goal of this project is to discover the mechanisms controlling blood vessel formation as a prerequisite to the development of superior therapies to attenuate diseases involving aberrant angiogenesis such as cancer and ocular maladies. New blood vessel formation in diseased tissues is dependent on a secreted protein called vascular endothelial growth factor (VEGF) and, in part, by its activation of a protein called ROCK2 which is expressed in cells lining the walls of blood vessels (endothelial cells [ECs]);however, the specific mechanism by which ROCK2 controls this process is largely unknown. In order to better determine if ROCK2 is a plausible drug target against blood vessel formation in diseased tissue, the following experiments have been proposed: #1 determining the role of ROCK2 in EC cell division, migration, survival, and in cell-to-cell and cell-to-environment interactions-all processes necessary for new blood vessel formation, (Aim #2) identifying morphological changes in EC structure that are regulated by ROCK2, and (Aim #3) determining the importance of ROCK2 in controlling the expression of genes which are involved in new blood vessel formation. Accomplishing the specific aims outlined in this proposal will provide the foundation required to determine if ROCK2 is an appropriate and potentially effective target for uncontrolled capillary formation in numerous diseases.
Diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, and more than 70 other known conditions are all characterized by excessive or insufficient blood vessel growth. The aims proposed in this project, which are designed to elucidate the role of a protein called ROCK2 in blood vessel formation, will provide a better understanding of the deregulation of cellular signaling in abnormal blood vessel formation. The findings from this project will lay a foundation for the development of more efficiently targeted therapeutics for these diseases.
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