Srinivasan Lab

My goals are to understand the molecular mechanisms regulating lymphatic and valvular endothelial cell development and maintenance.

The mammalian lymphatic vasculature is important for returning the extravasated plasma fluids in tissue space back to blood circulation, absorption of digested lipids from the intestine and in immune surveillance. Lymphedema is a disfiguring and mobility restricting disease that results due to the abnormal functioning of the lymphatic vasculature. Lymphedema is a common disorder that results either due to mutations in genes that regulate lymphatic vascular development or more often due to infection or surgical damage to the lymphatic vessels. Lymphatic vasculature is also considered as a major route for tumor metastasis especially melanoma and breast cancer. Despite its importance, diagnosis of lymphatic disorders and the identification of new targets to treat those ailments are limited.

Valves regulate the unidirectional flow of fluids (blood or lymph) in the mammalian vascular system. Valves are present in the heart, veins and the lymphatic vessels and are crucial for the normal physiology of the cardiovascular system. In addition, there is also a unique type of valve known as the lymphovenous valve that regulates the return of lymph fluid including all of the digested lipids (approximately 2 liters per day in an average human being) back to venous circulation.

Congenital cardiac valve defects are common causes for childhood mortality and morbidity. Calcification of cardiac valves occurs in approximately 10% of people who are at least 65 years old. This leads to valvular stenosis that could result in atherosclerosis, pulmonary edema, thromboembolism, cardiac hypertrophy and sudden cardiac death. A high-fat diet is known to aggravate this disease. Infection and non-infection (cancer) related endocarditis also damages cardiac valves.

In the aging population a range of venous valve defects such as spider veins, varicose veins and venous insufficiency are common. Incompetent venous valves results in ineffective blood flow causing pooling of blood and thrombosis. This result in embolism, problems in wound healing and tissue necrosis. In severe cases this leads to the stroke or amputation of the limbs.

Defects in formation or functioning of lymphatic valves cause lymphedema. Lymphectomy performed during breast cancer treatment frequently damages both lymphatic vessels and valves resulting in lymphedema.

No information is currently available regarding lymphovenous valves in human disease although using mouse models, we have recently demonstrated that defects in these valves could lead to lymphedema and chylothorax (Geng, et al 2016). We believe that similar to the other cardiovascular valves they are likely to undergo aging related degeneration.

Despite their importance our understanding of valves during normal development and in disease is limited. With increase in the median age of the general population and with improving treatment options for cancer we have an urgent need to better understand the biology of valves and develop treatment methodologies to treat valve disorders beyond conventional synthetic replacement valves that are associated with significant mortality and morbidity.

Despite their differences, the development of both lymphatic and valvular endothelial cells is regulated by a common set of transcription factors and signaling molecules. Our goal is to understand these molecular mechanisms and translate this knowledge into effective treatments.

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