V.P. Eswarakumar, Ph.D.
Assistant Professor of Orthopaedics and Pharmacology
Joined Yale in 2007
|1999 ||Ph.D. Madurai Kamaraj University, Madurai, India.
Gold Medal for Outstanding Performance in Behavioral Studies during M.Sc., 1989. Sponsored by Dr. G.J. Phanual Endowment, Madras Christian College, Chennai, India.
Young Researcher Award, for oustanding research on Biological Rhythms, 1989. Sponsored by Dr. P.J. Sanjeevaraj Endowment, Madras Christian College, Chennai, India.
Young Scientist Award and Medal for generating a potential therapeutic antibody for autoimmune diseases and modeling the 3-D structure of the antigen binding domain during Ph.D., 1996. Sponsored by the Indian Immunology Society and the National Institute of Immunology, New Delhi, India.
Annual Author Prize Winner of the Year 2005 for the most read review article of the journal on FGF signaling. Sponsor: Cytokine & Growth Factor Reviews.
The research focus of my lab is to explore the molecular and cellular mechanism of fibroblast growth factor receptor (FGFR) signaling in craniofacial development, branching morphogenesis and mineral homeostasis. We are currently pursuing three projects in our laboratory.
Project 1 involves the mechanism of FGFR signaling in craniofacial development. The mammalian skull is composed of 22 separate bones which grow at specialized joints called 'sutures' to accommodate the rapidly growing brain during early development. FGFR mutations cause the premature fusion of cranial sutures prior to the completion of brain growth, a condition called craniosynostosis. We have made several animal models by 'knock-in' gene targeting to explore the mechanism of craniosynostosis caused by FGFR-2 mutations that includes the first animal model for Crouzon-type craniosynostosis syndrome. We are exploring the FGF-responsive transcription factors and signaling molecules that are activated in cranial osteoblast cells using genomic and proteomic approaches.
Project 2 involves the mechanism of FGFR signaling in branching morphogenesis. FGFRs are expressed as two major isoforms, 'b' and 'c'. The b isoforms are expressed in epithelial cell layers, whereas the c isoforms are expressed in the mesenchymal tissues. While the c isoforms play a major role in bone development, the b isoforms play a critical role in the branching morphogenesis of organs. We are using salivary gland development as a model to explore the mechanism of FGFR signaling in branching morphogenesis. We are employing 3-D organ culture, as well as biochemical, cell biological and genomic approaches, to understand the process of branching morphogenesis.
Project 3 involves the mechanism of Klotho-FGFR signaling in calcium and phosphate homeostasis. FGF23 is the largest member of the FGF family and is produced by osteoblasts in bone, released into the circulation like an endocrine hormone and is able to regulate phosphate and calcium re-absorption in the kidney. FGF23 requires Klotho to signal via FGFRs to mediate its endocrine function. Klotho is a single pass type I membrane protein highly expressed in the distal convoluted tubules of kidney and interacts with FGFRs. However, which of the FGFR isoforms that Klotho interacts to regulate phosphate/calcium homeostasis is not known. Therefore, we are creating a genetic tool to identify FGFRs in the distal convoluted tubules of kidney that interact with Klotho and to explore the signaling mechanisms that are involved in calcium and phosphate homeostasis.
1. Eswarakumar VP and Schlessinger J. Skeletal overgrowth is mediated by deficiency in a specific isoform of fibroblast growth factor receptor-3. Proc Natl Acad Sci U S A. 104(10):3937-42 (2007)
2. Fox MA, Sanes JR, Borza D, Eswarakumar VP, Fassler R, Hudson B, John SW, Ninomiya Y, Pedchenko V, Rheault M, Sado Y, Segal Y, Werle MJ and Umemori H. Distinct target-derived signals organize formation, maturation and maintenance of motor nerve terminals. Cell 129(1):179-93 (2007)
3. Eswarakumar VP, Özcan F, Lew ED, Bae JH, Tomé F, Booth CJ, Adams DJ, Lax I, and Schlessinger J. Attenuation of signaling pathways stimulated by pathologically activated FGFR2 mutants prevents craniosynostosis. Proc Natl Acad Sci U S A. 103 (49), 18063-8 (2006)
4. Rohmann E, Brunner H, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Emerouglu M, Leroy J, Li Y, Becker C, Lehnerdt K, Cremers CWRJ, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, Bockhoven HV, and Wollnik B. Mutations in different components of FGF-signalling in LADD syndrome. Nature Genetics 38, 414-417 (2006)
5. Eswarakumar VP, Lax I and Schlessinger J. Cellular Signaling by FGF receptors. Cytokine Growth Factor Rev. 16(2):139-49 (2005)
6. Eswarakumar VP, Horowitz MC, Locklin R, Morriss-Kay GM and Lonai P. A gain of function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Proc Natl Acad Sci U S A. 101(34):12555-60 (2004)
7. Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM, Lonai P. The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development. 129(16): 3783-93 (2002)
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V.P. Eswarakumar, Ph.D.
Department of Orthopaedics & Rehabilitation
Yale University School of Medicine
330 Cedar Street
PO Box 208071
New Haven, CT 06520
330 Cedar Street, TMP 504
New Haven, CT 06520