Michael S. Lan, Ph.D.
Gene regulation, pancreatic endocrine cell growth and differentiation, genetic and cellular replacement therapy of diabetes mellitus.
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Michael S. Lan, Ph.D.
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Research Projects
| Neuroendocrine cell differentiation - We study a transcription factor, INSM1/IA-1, in | |
| pancreas and brain development. INSM1 is a novel zinc-finger DNA-binding protein primarily expressed in fetal pancreas, brain, and tumors of neuroendocrine origin, but not in normal adult tissues. Functional analyses revealed that INSM1 is a transcriptional repressor and its DNA-binding domain recognizes 5’-flanking promoter region of multiple target genes including NeuroD/beta2, insulin, and INSM1 itself. Global INSM1 gene deletion caused failure of beta cell development suggesting that INSM1 is essential for pancreatic endocrine cell. More experimental strategies are employed to elucidate the biological function of INSM1. |
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| Developmental Regulation of the Insulin Gene - In this proposal we aim to study: 1) Molecular mechanisms of how the transcriptional complex contributes to the INSM1 repressor activity. The gain of function experiment will be conducted using modified rat insulin I promoter linked to the INSM1 cDNA. 2) We will test the effects of loss of INSM1 expression specifically in beta cells. 3) We will analyze an additional INSM1 binding site on the insulin gene variable number of tandem repeats (INS-VNTR) region. We will employ the biochemical methods and a unique dual reporter transgenic animal model to study the mechanism of differential allelic haplotype-dependent insulin expression levels. | |
| Islet cell growth and differentiation of fetal islet-like cell clusters (ICCs) - We are interested in developing a culture system for pancreatic stem cells to differentiate into the insulin producing cells. We have found that stem cells derived from fetal pancreas possess | |
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great potential to proliferate and differentiate into islets as islet-like cell clusters (ICCs). Efforts were placed on stimulating ICCs to proliferate and differentiate into islets by growth hormones and genetic engineered transcription factors into precursor cells that could promote them to convert into hormone producing endocrine cells.
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Promoter-Specific Cancer Gene Therapy - Neuroendocrine tumor represents a collection of rare kinds of tumors that predominantly express INSM1 transcription factor. We studied the INSM1 promoter regulation in neuroendocrine tumors. Delivery of a construct consists of INSM1 promoter linked to the HSV-tk suicide gene into euroendocrine tumor is capable of suppressing the tumor growth after ganciclovir treatment. Currently, new strategy is employed to enhance the INSM1 promoter activity in neuroendocrine tumors. The modified INSM1 promoter could be of great value for cancer gene therapy.
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Faculty List Order:
780
