Potential for cell therapy in Parkinson's disease using genetically programmed human embryonic stem cell-derived neural progenitor cells.
Ambasudhan R, Dolatabadi N, Nutter A, Masliah E, Mckercher SR, Lipton SA
J Comp Neurol. 2014 Aug 15;522(12):2845-56
Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells.
Zhu S, Ambasudhan R, Sun W, Kim HJ, Talantova M, Wang X, Zhang M, Zhang Y, Laurent T, Parker J, Kim HS, Zaremba JD, Saleem S, Sanz-Blasco S, Masliah E, McKercher SR, Cho YS, Lipton SA, Kim J, Ding S
Cell Res. 2014 Jan;24(1):126-9
Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription.
Ryan SD, Dolatabadi N, Chan SF, Zhang X, Akhtar MW, Parker J, Soldner F, Sunico CR, Nagar S, Talantova M, Lee B, Lopez K, Nutter A, Shan B, Molokanova E, Zhang Y, Han X, Nakamura T, Masliah E, Yates JR, Nakanishi N, Andreyev AY, Okamoto S, Jaenisch R, Ambasudhan R, Lipton SA
Cell. 2013 Dec 5;155(6):1351-64
Direct lineage reprogramming to neural cells.
Kim J, Ambasudhan R, Ding S
Curr Opin Neurobiol. 2012 Oct;22(5):778-84
Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions.
Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S
Cell Stem Cell. 2011 Aug 5;9(2):113-8
Reprogramming of human primary somatic cells by OCT4 and chemical compounds.
Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K, Ding S
Cell Stem Cell. 2010 Dec 3;7(6):651-5
A chemical platform for improved induction of human iPSCs.
Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm HS, Hao E, Hayek A, Ding S
Nat Methods. 2009 Nov;6(11):805-8
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Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation.
Akhtar MW, Sanz-Blasco S, Dolatabadi N, Parker J, Chon K, Lee MS, Soussou W, McKercher SR, Ambasudhan R, Nakamura T, Lipton SA
Nat Commun. 2016;7:10242
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
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.