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Developmental regulation of the insulin gene

Abstract:

Insulin gene regulation plays an important role in islet cell development and diabetes. The objective of this research project is to characterize a novel zinc-finger transcription factor (INSM1/IA-1) as a negative regulator of the insulin gene in developing pancreatic beta cells. The INSM1 zinc-finger transcription factor is an early embryonic differentiation antigen of the pancreas. INSM1 expression is restricted in both the fetal pancreas and insulinomas. Functional studies reveal that INSM1 is a transcriptional repressor that represses target genes closely associated with pancreatic endocrine cell functions. Both EMSA and transient transfection data support that INSM1 is a negative regulator of the insulin promoter. The studies outlined in this proposal will focus on issues regarding the biological function of INSM1 in insulin gene regulation. Aim 1: the applicant will work towards the molecular mechanisms of how the transcriptional complex contributes to the INSM1 repressor activity. The gain of function experiments will be conducted in normal islets and a transgenic animal model using a modified rat insulin I promoter linked to the INSM1 cDNA. It is hypothesized that the over-expression of INSM1 in beta cells may suppress insulin gene expression, subsequently rendering hyperglycermia. We will examine the effects of INSM1 over-expression during fetal pancreas development. The results of this experiment will reveal that INSM1 could suppress insulin gene expression in the early stages of beta cell differentiation. Aim 2: the applicant will generate a conditional knockout INSM1 animal. A floxed INSM1 targeted animal will be crossed with RIP-cre transgenic mice. This animal model will address the biological function of INSM1 specifically in insulin producing cells. Aim 3: We have discovered additional INSM1 binding site on the insulin gene variable number of tandem repeats (INS-VNTR) region. It is likely that INSM1 could modulate insulin gene expression through VNTR in a haplotype-dependent manner. Biochemical methods are proposed to examine the interaction of INSM1 with class I and III insulin locus haplotypes. We also design a unique floxed transgenic animal model to reveal the expression patterns of class I and III INS-VNTR as well as the functional effects of INSM1 on the transgenic islet-like cell clusters. These studies could shed light on the potential mechanism of differential allelic haplotype-dependent insulin expression levels. In summary, the outcomes of this proposal could provide important advances in insulin gene regulation and pancreas development.