Shivakumar Vasanth, Ph.D.

Harvard Medical School

Instructor in Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Investigator

Research Summary

Center/Research Area Affiliations

Biography

Dr. Vasanth’s research focuses on understanding the molecular pathogenesis of multiple human genetic disorders with in vitro and in vivo models. Currently, he aims to identify the underlying mechanism of Fuchs' endothelial corneal dystrophy (FECD). This condition results in a progressive loss of corneal endothelial cells with age, and it is exacerbated by oxidative stress. Dr. Vasanth’s projects aim to understand: 1) aberrant DNA damage response and repair mechanisms that play roles in the progressive loss of corneal endothelial cells; 2) mechanisms of pathogenesis that are related to abnormal mitochondrial dynamics due to oxidative stress; and 3) the link between the repeat expansions and oxidative stress-induced loss of corneal endothelial cells.

Download his CV [PDF] or biosketch [PDF] for more information.

Education

B.Sc., Biochemistry, University of Madras, India (1998)
M.Sc., Biotechnology, Pondicherry University, India (2000)
Ph.D. Cell and Molecular Biology, Kent State University (2007)

Postgraduate Training

Postdoctoral Fellowship, National Institute of Environmental Health Sciences, National Institutes of Health (2011)
Postdoctoral Fellowship, Center for Human Disease Modeling, Duke University (2014)
Postdoctoral Fellowship, Department of Ophthalmology, Johns Hopkins University (2015)

Honors

2016-2017: Co-principal Investigator, Eversight Vision Research Grant
2015: National Eye Institute Travel Grant, 2015 ARVO Annual Meeting
2005: Joint Third Prize in the category of Pfizer Predoctoral Awards for Excellence in Renal Research at Experimental Biology meeting, San Diego, CA

His Story

Corneal Endothelium

The corneal endothelium is the innermost layer of the cornea that is comprised of highly differentiated endothelial cells. The major function of the corneal endothelium is to maintain the transparency of the cornea by controlling the hydration of stroma and acting as a barrier that regulates the movement of nutrients into the cornea. Corneal endothelial dysfunctions arise due to a variety of etiology and during different stages of life.

What is Fuchs' Endothelial Corneal Dystrophy?

Fuchs' endothelial corneal dystrophy (FECD) is a bilateral ophthalmic disorder that results in progressive loss of corneal endothelial cells and corneal edema, requiring corneal transplantation. Clinical signs include blurry vision, glare, and decreased night vision with possible halos around lights. These symptoms usually become clinically evident in the fourth and fifth decades of life. Initially, the patient notices blurred vision, then symptoms progress as the disease advances through its stages—often ending in blindness.

Prevalence of FECD

FECD can be divided into early-onset (manifesting in the 3rd decade of life) and late-onset (manifesting in the 5th decade of life, on average). Both early- and late-onset forms have female predominance at a ratio of 2.5-3:1. In the United States, the prevalence is about 4% of the population over the age of 40.

Significance

FECD is one of the most common causes of blindness from corneal swelling and a second-most common cause of corneal transplants in the United States. Because it is unclear what triggers corneal endothelial cells to die in FECD, there is no effective treatment, and corneal transplantation is the only currently available measure to restore lost vision.

What Causes FECD?

Multiple mutations have been identified in cases with familial inheritance. However, these mutations account only for a small fraction of FECD cases. Recently, multiple studies have identified an association of the expansion of trinucleotide CTG repeat in the intron of TCF4 in two-thirds of FECD cases in the United States. A significant effort is being invested in understanding the functional effect of the expansion of this region in the genome that can explain the pathology of FECD.

Ula V. Jurkunas' laboratory at Schepens Eye Research Institute of Mass. Eye and Ear is studying how oxidative stress causes molecular and cellular damage in the susceptible FECD endothelium. These studies are significant because understanding the key regulators of antioxidant defense and oxidative stress-induced cellular damage may facilitate development of pharmacotherapeutic treatment for FECD patients.

Why is Research Important?

Currently, corneal transplantation is the only effective treatment for FECD. However, it carries substantial economic, medical, and social burdens, including the costs of the surgery, management of associated graft complications and failures, lifelong dependence on steroids, and the risk of glaucoma. There is a significant unmet need to improve the understanding of the mechanism of FECD and to develop pharmacotherapeutic interventions that could prevent premature endothelial cell loss.

Projects

Research Interests

  • Mechanism of pathogenesis of Fuchs' endothelial corneal dystrophy (including the genetics of FECD and the relevance of CTG repeat expansion to the disease pathology)
  • Functional modeling of human genetic diseases in zebrafish and mice

Mechanism of DNA Damage Response and Repair in FECD

Ula V. Jurkunas laboratory at Mass. Eye and Ear has reported an increase in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) damage in FECD. Further modeling of the disease in human corneal endothelial cells (HCEnC) with menadione (that induces oxidative stress by increasing superoxide radicals) showed a similar increase in nDNA and mtDNA in HCEnCs. Dr. Vasanth's current project aims to identify the aberrant DNA damage response and repair mechanisms in FECD through in vitro (cell lines) and in vivo modeling (mice).

Understanding the Relevance of Trinucleotide Repeat Expansion

Trinucleotide repeat expansion in TCF4 accounts for a significant genetic association in two-thirds of FECD cases. Using FECD ex vivo specimens from endothelial keratoplasty and FECD cell lines, Dr. Vasanth aims to understand the role of the expansion in FECD.

Current Research Funding

2016
Eversight Center for Eye and Vision Research

Publications

H-index

9 (Google Scholar, as of August 2017)

Selected Publications

Below is a list of selected publications. View his publications on PubMed, Google Scholar, or ORCID.

  1. Allen O. Ehgrari, Shivakumar Vasanth, Jiangxia Wang, Farnoosh Vahedi, S. Amer Riazuddin, and John D. Gottsch. CTG18.1 expansion in TCF4 increases likelihood of transplantation in Fuchs Corneal Dystrophy. Cornea. 2017 Jan;36(1):40-43
  2. Shahid Y. Khan, Shivakumar Vasanth, Firoz Kabir, John D. Gottsch, Arif O. Khan, Raghothama Chaerkady, Mei-Chong W. Lee, Carmen C. Leitch, Zhiwei Ma, Julie Laux, Rafael Villasmil, Shaheen N. Khan, Sheikh Riazuddin, Javed Akram, Robert N. Cole, C. Conover Talbot, Nader Pourmand, Norann A. Zaghloul, J. Fielding Hejtmancik, and S. Amer Riazuddin. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nature Communications. 7, Article number: 10953; 06 April 2016.
  3. Shivakumar Vasanth, Allen O. Ehgrari, Briana C. Gapsis, Jiangxia Wang, Nicholas F. Haller, Walter J. Stark, Nicholas Katsanis, S. Amer Riazuddin, and John D. Gottsch. Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of Fuchs Corneal Dystrophy. Investigative Ophthalmology and Visual Science. 2015 Jul; 56(8): 4531-6
  4. Claudia M.B. Carvalho*, Shivakumar Vasanth*, Marwan Shinawi, Melissa B. Ramocki, Chester W. Brown, Jesper Graakjaer, Anne-Bine Skytte, Angela M. Vianna-Morgante, Ana C. V. Krepischi, Carolyn Bay, Gayle Simpson, La Donna Immken, Aleck Kyrieckos, Cynthia Lim, Sau Wai Cheung, Carla Rosenberg, Nicholas Katsanis, and James R. Lupski. Dosage changes of a segment at 17p13.1 leads to intellectual disability and microcephaly due to complex genetic interaction of multiple genes. American Journal of Human Genetics. 2014, Nov 6; 95(5): 565-578
  5. Edwin C. Oh, Shivakumar Vasanth and Nicholas Katsanis. Metabolic regulation and energy homeostasis through the primary cilium. Cell Metabolism. 2015 Jan 6; 21(1):21-31.