Dr. Yaakov Nahmias is a current Instructor in Surgery and Bioengineering at Harvard Medical School and seeks to establish himself as an independent investigator in the fields of regenerative medicine and BioMEMS. To that end, Dr. Nahmias submits this five years Career Development Award under the sponsorship of Dr. Mehmet Toner, director of the BioMEMS Resource Center and Dr. David Scadden, co- director of the Harvard Stem Cell Institute, both at Harvard Medical School. This award consists of a detailed career development plan which includes: 1) intensive training in microfabrication, 2) academic courses in Harvard and MIT, 3) seminars and lectures, and 4) advisory committee guidance. Research environment includes state-of-the-art facilities at Massachusetts General Hospital consisting of over 7000 sq ft of research and office space with adjacent cleanroom (class 1000), animal, and characterization facilities. The overall goal of this proposal is to elucidate and control the molecular mechanisms (transcription factor networks) underlying the differentiation of stem cells toward the hepatic phenotype.
Our specific aims are to: 1) develop and characterize GFP-responsive mouse ES cell lines to major endodermal transcription factors;2) microfabricate a living cell array for the culture of ES cells, and 3) elucidate and control the transcription factor networks regulating the differentiation of ES cell-derived endoderm toward the hepatic phenotype using soluble signals. We expect to: (a) develop multiple mouse embryonic stem cell lines with GFP- responsive transcription factor elements, (b) elucidate key genetic pathways underlying the differentiation of ES-derived endoderm toward the hepatic phenotype, and (c) provide new avenues to explore the differentiation potential of embryonic stem cells for scientific and clinical applications. One of the major challenges in the field today is the scarcity of functional human hepatocytes as the cells are notoriously difficult to proliferate in vitro. The treatment of liver failure would require around (10)10 hepatocytes. Treatments on this scale necessitate the development of alternative cellular sources that can potentially produce hepatocytes in high yields and large cell numbers.
|Zhu, Beili; Smith, James; Yarmush, Martin L et al. (2013) Microfluidic enrichment of mouse epidermal stem cells and validation of stem cell proliferation in vitro. Tissue Eng Part C Methods 19:765-73|
|Avior, Yishai; Bomze, David; Ramon, Ory et al. (2013) Flavonoids as dietary regulators of nuclear receptor activity. Food Funct 4:831-44|
|Shulman, Maria; Nahmias, Yaakov (2013) Long-term culture and coculture of primary rat and human hepatocytes. Methods Mol Biol 945:287-302|
|Bao, Ji; Fisher, James E; Lillegard, Joseph B et al. (2013) Serum-free medium and mesenchymal stromal cells enhance functionality and stabilize integrity of rat hepatocyte spheroids. Cell Transplant 22:299-308|
|Ezra, Elishai; Keinan, Eliezer; Mandel, Yossi et al. (2013) Non-dimensional analysis of retinal microaneurysms: critical threshold for treatment. Integr Biol (Camb) 5:474-80|
|Spokoini, Rachel; Moldavski, Ofer; Nahmias, Yaakov et al. (2012) Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. Cell Rep 2:738-47|
|Izamis, Maria-Louisa; Sharma, Nripen S; Uygun, Basak et al. (2011) In situ metabolic flux analysis to quantify the liver metabolic response to experimental burn injury. Biotechnol Bioeng 108:839-52|
|Goldwasser, Jonathan; Cohen, Pazit Y; Lin, Wenyu et al. (2011) Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism. J Hepatol 55:963-71|
|Shulman, Maria; Cohen, Merav; Soto-Gutierrez, Alejandro et al. (2011) Enhancement of naringenin bioavailability by complexation with hydroxypropyl-Î²-cyclodextrin. [corrected]. PLoS One 6:e18033|
|Goldwasser, Jonathan; Cohen, Pazit Y; Yang, Eric et al. (2010) Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha. PLoS One 5:e12399|
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