About the Project
Regulation of proteostasis is critical for maintaining tissue homeostasis. Autophagy, a major intracellular degradation pathway essential for cellular and energy homeostasis, functions in the clearance of misfolded proteins and damaged organelles. It acts primarily as a cell survival process, such as during starvation by recycling cytosolic components to compensate for nutrient deprivation. This process is regulated by mammalian target of rapamycin (mTOR) and mTOR-independent pathways that are amenable to chemical perturbations. Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration. Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy, and therefore, stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models. Emerging evidences indicate that compromised autophagy contributes to the etiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity. Over the last decade, autophagy has thus become an important biological process to study owing to its implications in various human physiological and pathological conditions, including development, immunity, cancer, neurodegeneration and longevity.
Although autophagy is evolutionarily conserved and is well characterized in yeasts, its regulation in the human system is not completely understood. Moreover, combining the knowledge of autophagy dysfunction and the mechanism of drug action in human disease-relevant cellular contexts may be rational for designing targeted therapy. Towards this, Dr Sovan Sarkar’s laboratory is working on the regulation and therapeutic application of autophagy in human disease-relevant cell types using human embryonic stem cells (hESCs) and disease-specific human induced pluripotent stem cells (hiPSCs).
Broad research themes in the laboratory are as follows:
(i) The role and regulation of autophagy in hESCs and in human disease-relevant cell types differentiated from hESCs.
(ii) The molecular mechanisms of mammalian autophagy in its role in cellular homeostasis, neurodegeneration, aging and metabolism.
(iii) Mechanisms of cellular degeneration and proteostasis in disease-affected human cell types derived from disease-specific hiPSCs.
(iv) Drug discovery in human disease-affected cell types derived from disease-specific hiPSCs.
Research projects will be in the areas of cell biology and biochemistry, and will incorporate the use of high-content and confocal microscopy, mass spectrometry, generation of hiPSCs by reprogramming, genome engineering in hESCs/hiPSCs, differentiation of hESCs/hiPSCs into various disease-relevant cell types, and compound screening, amongst others. PhD students will be encouraged to work on one or multiple projects at the interface of fundamental biology and translational science, and will be supervised directly by the principal investigator as well as the postdocs in the lab. Since Dr Sovan Sarkar collaborates with many research groups worldwide, the students will get an opportunity to work with international scientists and travel to their laboratories as well when required.
Further details about the principal investigator or research can be found at www.birmingham.ac.uk/sovan-sarkar or http://www.mit.edu/~sarkar/. If you are interested to discuss about the research projects, please write to Dr Sovan Sarkar at [Email Address Removed]
References
Maetzel M.*, Sarkar S.*, Wang H.*, Abi-Mosleh L., Xu P., Cheng A.W., Gao Q., Mitalipova M. and Jaenisch R. (2014) Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick type C patient-specific iPS cells. Stem Cell Reports 2(6): 866-880. *Equal contribution
Sarkar S. (2013) Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: Autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochemical Society Transactions 41(5): 1103-1130.
Sarkar S., Carroll B., Buganim Y., Maetzel D., Ng A.H.M., Cassady J.P., Cohen M.A., Chakraborty S., Wang H., Spooner E., Ploegh H., Gsponer J., Korolchuk V.I. and Jaenisch R. (2013) Impaired autophagy in the lipid storage disorder Niemann-Pick type C1 disease. Cell Reports 5(5): 1302-1315.
Sarkar S., Korolchuk V.I., Renna M., Imarisio S., Fleming A., Williams A., Garcia-Arencibia M., Rose C., Luo S., Underwood B.R., Kroemer G., O’Kane C.J. and Rubinsztein D.C. (2011) Complex inhibitory effects of nitric oxide on autophagy. Molecular Cell 43(1): 19-32.
Williams A.*, Sarkar S.*, Cuddon P.*, Ttofi E.K., Saiki S., Siddiqi F.H., Jahreiss, L., Fleming A., Pask D., Goldsmith P., O’Kane C.J., Floto R.A. and Rubinsztein D.C. (2008) Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chemical Biology 4(5): 295-305. *Equal contribution.
Sarkar S., Perlstein E.O., Imarisio S., Pineau S., Cordenier A., Maglathlin R.L., Webster J.A., Lewis T.A., O’Kane C.J., Schreiber S.L. and Rubinsztein D.C. (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nature Chemical Biology 3(6): 331-338.
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