Rajesh Ambasudhan

Rajesh Ambasudhan, Ph.D.[La Jolla]

  • Research

    Dr. Ambasudhan uses human stem cell models to study neurodegenerative diseases and in developing therapies.

  • Biography



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Rajesh Ambasudhan's Research Focus

Autism Spectrum Disorders, Neurodegenerative and Neuromuscular Diseases, Parkinson's Disease, Stroke

Our current efforts are largely focused on therapeutic development in neurodegenerative and mitochondrial disorders. To facilitate this we develop "human models" of these diseases using human induced pluripotent stem cells (hiPSC), human induced neurons (hiN) and hiPSC-derived neural 3D cultures (brain organoids). We use these platforms and cutting edge techniques for studying the underlying disease mechanisms and in translating them for drug discovery and in developing cellular therapeutics.

Rajesh Ambasudhan's Research Report

Rajesh Ambasudhan
We focus on gaining deeper insights into the biology of neurodegenerative diseases, so as to translate such knowledge into effective therapies. Several studies have acknowledged the role of oxidative stress, mitochondrial dysfunction, metabolic changes and aberrant proteostasis in the pathology of these diseases. However, it is still unclear what triggers these events and how are they orchestrated to cause neuronal death. Toward addressing these questions and devising therapies we take an interdisciplinary approach by integrating neuroscience, translational stem cell research, and drug discovery. We develop hiN, hiPSC, and hiPSC-derived brain organoids-based “human models” of neurodegenerative diseases and interrogate them to understand the disease mechanisms by using cutting edge technologies like optogenetics, gene targeting, advanced imaging etc. Such knowledge is then translated into devising novel therapies (cell therapy, small molecule drugs). Using these approaches we recently showed how environment and genes conspire in orchestrating aberrant cellular events leading to the apoptotic cell death in patient hiPSC-derived A9 dopaminergic neurons, the major cell type affected in Parkinson’s disease (PD) (Cell, 2013), and by targeting such “events” in an HTS effort we discovered novel lead compounds for therapeutic development in PD.

The findings from this study suggested that mitochondrial dysfunction resulting from the oxidative modifications of certain key proteins could be one of the earliest cellular events in PD pathogenesis. Consequently, our recent efforts are primarily invested in teasing out these events and in understanding the role that mitochondria and oxidative stress play in eliciting neurodegenerations. To further support these efforts we have also developed human reprogrammed-cell models of genetic mitochondrial disorders (MELAS, LHON) that involve neurodegenerations as their major pathology. Using these human mode l systems and by complementing them with in vivo studies in rodent models (through collaborations), we have started to learn how redox modifications of certain mitochondrial proteins can influence the metabolic intermediates leading to epigenetic changes in the genome, in the context of neuronal degenerations. These basic biology insights are also helping us in manipulating stem cells for developing cell therapeutics or devising high-throughput screening platforms for drug discovery for these diseases. We are supported by grants from UMDF, CIRM and the NIH, and collaborations from within the academics and from industry.

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