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Home - Science - Scientist Directory - Srinivasan, Sathish

Sathish Srinivasan, Ph.D.

Associate Member
Cardiovascular Biology Research Program

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My 101

The heart pumps blood, which carries oxygen and other nutrients throughout the body. Plasma is released from blood vessels to nourish the tissues. The lymphatic system functions to return this tissue fluid to blood circulation. A condition called lymphedema results when the lymphatic vasculature is damaged. Accumulating fluids cause swelling in the tissues that can lead to infections, inflammation and pain. Surgical damage to lymphatic vessels causes lymphedema in millions of people every year. Currently, only conservative treatments like massage and compression bandages are available. In my lab, we are studying the genes and signaling pathways responsible for the development and growth of the lymphatic vasculature.

We also focus on the role of the valves that regulate fluid flow within the vascular system. Valves are present within lymphatic vessels, veins and in the heart. A range of diseases such as spider veins, varicose veins, lymphedema and cardiac valve defects occur if the valves are not formed correctly or if they are damaged by injury or disease. By studying the genes responsible for the formation or functioning of valves, we can develop better strategies to repair these problems.

Research

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.

Brief CV

Education
B.Tech., Anna University, Chennai, India, 1999
Ph.D., Tulane University Medical Center, New Orleans, LA, 2003

Honors and Awards
2003 Morris F. Shaffer and Margret H.D. Smith-Shaffer Award for Excellence in Research, Tulane University, New Orleans, LA
2003 Keystone Symposia Scholarship, Keystone Symposium on Molecular Targets for Cancer Therapy, Banff, Canada
2005 Award for Best Scientific Talk, Vanderbilt University retreat on developmental biology, Paris Landing State Park, TN
2006 Outstanding Poster Award, Developmental vascular biology workshop II, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2008 Travel Award, Developmental vascular biology workshop III, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2010 Travel Award, Developmental vascular biology workshop IV, North American Vascular Biology Organization (NAVBO), Asilomar, CA
2017 Fred Jones Award for Scientific Achievement

Membership
North American Vascular Biology Organization
Society for Developmental Biology
American Heart Association

 

Joined OMRF Scientific Staff in 2013

 

Publications

View more publications

Recent Publications

Chen D, Geng X, Lapinski PE, Davis MJ, Srinivasan RS, King PD. RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice. Development, 2020 November, PMID: 33144395, PMCID: PMC7746672

Cha B, Ho YC, Geng X, Mahamud MR, Chen L, Kim Y, Choi D, Kim TH, Randolph GJ, Cao X, Chen H, Srinivasan RS. YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling. Development, 2020 October, PMID: 33060128, PMCID: PMC7758626

Geng X, Yanagida K, Akwii RG, Choi D, Chen L, Ho Y, Cha B, Mahamud MR, Berman de Ruiz K, Ichise H, Chen H, Wythe J, Mikelis CM, Hla T, Srinivasan RS. S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling. JCI Insight, 2020 June, PMID: 32544090, PMCID: PMC7453895

Selected Publications

Cha B, Geng X, Mahamud MR, Fu J, Mukherjee A, Kim Y, Jho EH, Kim TH, Kahn ML, Xia L, Dixon JB,  Chen H, Srinivasan RS (2016). Mechanotransduction activates canonical Wnt/beta-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev. (cover image) 30(12):1454-69. PMID: 27313318 PMCID: PMC4926867

Geng X, Cha B, Mahamud MR, Lim KC, Silasi-Mansat R, Uddin MK, Miura N, Xia L, Simon AM, Engel JD, Chen H, Lupu F, Srinivasan RS (2016). Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development. Dev Biol. (cover image), 409(1):218-33. PMID: 26542011 PMCID: PMC4688075

Srinivasan RS, Escobedo N, Yang Y, Interiano A, Dillard ME, Finkelstein D, Mukatira S, Gil HJ, Nurmi H, Alitalo K, Oliver G. The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev. 2014 Oct 1;28(19):2175-87. PMID: 25274728 PMCID: PMC4180978

Srinivasan RS, Oliver G. Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes Dev. 2011 Oct 15;25(20):2187-97. PMCID: PMC3205588

Srinivasan RS, Geng X, Yang Y, Wang Y, Mukatira S, Studer M, Porto MP, Lagutin O, Oliver G. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 2010 Apr 1;24(7):696-707. PMID: 22012621 PMCID: PMC3205588

Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM, Oliver G. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007 Oct 1;21(19):2422-32. PMID: 17908929 PMCID: PMC1993873

Contact

Cardiovascular Biology Research Program, MS 45
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

Phone: (405) 271-3550
Fax: (405) 271-3137
E-mail: sathish-srinivasan@omrf.org

Lab Staff

Xin Geng, Ph.D.
Staff Scientist

Yen Chun Ho, Ph.D.
Postdoctoral Fellow

Lijuan Chen
Research Assistant

Anita James
Administrative Assistant IV

 

News from the Srinivasan lab

Dr. Srinivasan in the Media

News from the Srinivasan lab

OMRF scientists discover potential target for lymphedema therapy
August 18, 2020

A recent discovery by scientists at OMRF could aid in the development of potential therapies for lymphedema.

OMRF scientists discover potential therapeutic target for lymphedema
December 11, 2019

Lymphedema is a disease characterized by dramatic and painful swelling in the limbs that often leads to infections.

New findings cast light on lymphatic system, key player in human health
October 16, 2018

OMRF researchers have broken new ground in understanding how the lymphatic system works.

OMRF names new board member and VP
April 14, 2017

OMRF hosted its semiannual meeting on Thursday.

$6.5 million grant will benefit cardiovascular research at OMRF
August 17, 2016

OMRF has received a 5-year NIH grant to continue heart and blood research.

Research identifies key player in lymphatic development
July 20, 2016

The new findings were published in the journal Genes & Development.

OMRF researcher awarded grant for lymphatic valve research
June 24, 2016

Sathish Srinivasan was awarded $1.77 million to investigate valve development.

OMRF researchers find that a biological “good guy” has a dark side
May 3, 2016

Enzyme thought harmless may be more dangerous than first believed

OMRF discoveries could lead to better treatment for lymphedema
December 7, 2015

There is currently no cure for lymphedema but new research might help manage it.

Controlling a protein may help prevent cancer from spreading
November 5, 2014

New OMRF research could improve cancer, diabetes treatments.

Dr. Srinivasan in the Media

New findings cast light on lymphatic system, key player in human health
EurekAlert.org

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