Ramesh, Tennore - University of Sheffield - Department of Neuroscience

个人简介

Dec 2008-Present Non-Clinical Lecturer, Academic Neurology, University of Sheffield, UK. 2004-2008 Founder, PALS Fund for ALS Drug Discovery, Ohio State University. Research scientist, Ohio State University, Columbus, OH 2000-8/2003 Founding Scientist and Chief Scientific Officer, ALS-TDF, Newton, MA, USA 1999- 2000 Scientist, Toxico and Pharmacogenomics, CuraGen Corporation, New Haven, CT, USA 1998-1999 Post-Doctoral Research Fellow, Human Genetics, University of Michigan, Ann Arbor, MI, USA 1996-1998 Post-Doctoral Research Fellow, Neurobiotechnology Center, Ohio State University, Columbus, OH, USA 1992-1996 PhD, Microbiology and Immunology, University of Kentucky, Lexington, KY, USA 1990-1992, MS, Animal Sciences, University of Kentucky, Lexington, KY 1982-1988 B.V.Sc (D.V.M), Madras Veterinary College, India

研究领域

Amyotrophic lateral sclerosis/Motor neuron disease (ALS/MND) is an adult onset motoneuron degenerative disease with a lifetime risk of ~1/1000. Approximately 80% of the cases are fatal within five years of diagnosis. There is no cure and only one FDA approved therapy, Riluzole has a minor effect on the progression of the disease. Mutations in genes such as SOD1, TDP-43, FUS, ANG, and VAPB also cause some forms of ALS although most forms of ALS is sporadic in nature. Despite the identification many genes causing ALS the exact mechanism of motor neuron toxicity is unclear, although a variety of mechanisms have been postulated. Identifying the upstream events that result in toxicity is critical to impact the disease process. Protein misfolding and cellular inclusions are a common theme in many neurodegenerative diseases including ALS. How protein misfolding contributes to toxicity, if protein inclusions are protective or detrimental is presently unknown. In most cases the accumulation of mutant proteins are not universally present in all cells but are restricted to specific cell types and also to specific regions in the CNS affected in the disease. Understanding the cause and mechanism of this toxic process is one of the focuses of my research. To understand disease process in this complex environment requires complex systems such as mice and more recently zebrafish. My lab utilises the power of mice and fish to study the pathogenic processes involved in neuronal death. Many transgenic models of ALS have been developed and have given valuable insight into the cellular players involved in disease process. My lab recently developed a transgenic zebrafish model of ALS with mutation in the sod1 gene. Transgenic sod1 zebrafish carrying mutant sod1 develop disease that is similar to that seen in mice and human. Additionally, these transgenic fish show early embryonic readout of mutant sod1 induced cellular stress response as early as 24 hours post-fertilization allowing us to study disease in these microscopic stages. Zebrafish are tropical fishes who are optically transparent in early embryonic and larval stages. Organogenesis is complete and freely swimming larvae hatch as early as 72 hours post-fertilization, providing a powerful tool to study tissue specific changes in diseased animals. Using GFP transgenic lines, we can visualize motoneurons and other spinal neurons cells in living animals. We can also analyze cell fate, axonal outgrowth and morphology, synapses (formation, maintenance, and activity), and motor behaviour. We can easily generate genetic mosaics to determine the autonomy of mutant sod1 and examine the cell autonomy of the mutant gene. This will allow us to readily address what cells contribute to the disease and the effect of mutant cells on wild-type motoneurons, an area, which is still in need of investigation. We employ molecular, cell biology, behavioural and genetic techniques to unravel the toxic mechanisms involved in ALS pathogenesis. Eventually, our goal is to test genes and drugs that can modify disease process to develop new therapies to treat ALS/MND.

近期论文

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Tennore Ramesh, Alison N. Lyon, Ricardo H. Pineda, Chunping Wang, Paul M. L. Janssen, Benjamin D. Canan, Arthur H. M. Burghes and Christine E. Beattie. 2010. A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. DMM. May 26. [Epub ahead of print] Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008; 9(1):4-15. Authorship withdrawn. Perjesi P, Kim T, Zharikova AD, Li X, Ramesh T, Ramasubbu J, Prokai L. 2003. Determination of clodronate content in liposomal formulation by capillary zone electrophoresis. J Pharm Biomed Anal.; 31(5):929-35. Clark JE, Brennan A, Ramesh TM, Heywood JA. 2002. Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study. Front Biosci.; 7:c83-96. Janson CG, Ramesh TM, During MJ, Leone P, Heywood J. 2001. Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis. J Hematother Stem Cell Res., 10(6):913-5