Melissa Thomas, M.D., Ph.D.

Transcriptional Regulation of Pancreatic Beta Cells

The primary goal of the Thomas laboratory is to identify novel methods to restore pancreatic beta-cell function and insulin production in patients with diabetes. The major research focus is to define molecular mechanisms of pancreatic beta-cell dysfunction and adaptation in cellular and animal model systems. Dr. Thomas’ interest in mechanisms of transcriptional regulation is of clinical relevance in light of the strong association between mutations of pancreatic beta-cell transcription factors and heritable forms of diabetes in humans. Current research projects in the laboratory include the following:

1. Regulation of pancreatic beta-cell function by coactivators. Dr. Thomas and colleagues discovered a novel coactivator, designated Bridge-1, that regulates the transcriptional activation of the insulin promoter. The laboratory has identified several transcriptional regulatory proteins that interact with Bridge-1 and is studying the mechanism by which Bridge-1 regulates insulin production. Dr. Thomas has developed mouse models of Bridge-1 dysregulation and their pancreatic and metabolic phenotypes are under analysis. The laboratory also is collaborating with a human geneticist to look for mutations in the Bridge-1 gene in individuals with adult-onset diabetes.

In collaboration with the Habener laboratory, Dr. Thomas is investigating the regulation of the MODY4 gene product PDX-1 by interactions with coactivators. The research team has identified mutations in PDX-1 that alter its interaction with the coactivator p300, providing a distinct mechanism by which mutations in the human pdx-1 gene can result in impaired insulin production and metabolic dysfunction.

2. Transcriptional regulation of adult pancreatic beta cells by morphogens A second series of studies in the laboratory is focused on the regulation of adult pancreatic beta-cell function by growth factors and morphogens that play essential roles in pancreas development, including hedgehog proteins. Dr. Thomas identified new functions for these signaling pathways in the transcriptional regulation of the insulin and pdx-1 genes that are essential for metabolic regulation in the adult. Dr. Thomas and colleagues are developing mouse models to elucidate mechanisms by which hedgehog signals regulate insulin production in the adult pancreas. In a collaborative project, studies of the regulation of insulin production by activin signaling via Smad transcription factors are ongoing.

3. Age-dependent changes in the transcriptional regulation of pancreatic beta cells. In a mouse model of inducible PDX-1 deficiency that Dr. Thomas developed, she discovered that younger but not older mice were able to compensate for the suppression of PDX-1 expression and maintain normal glucose homeostasis. In contrast older mice were susceptible to the suppression of PDX-1 expression and developed inducible hyperglycemia. She extended those studies to identify an inbred mouse strain in which younger mice were susceptible to the suppression of PDX-1 expression, suggesting that distinct heritable phenotypes exist that confer susceptibility to or compensation for PDX-1 deficiency. The laboratory is characterizing age-dependent beta-cell dysfunction in animal models with the goal of identifying changes in the transcriptional regulation of pancreatic beta cells that may confer a predisposition to the development of diabetes in older individuals.

4. Regulatory themes of adult pancreatic beta-cell adaptation and dysfunction. This exploratory collaborative project was designed to define regulatory themes of pancreatic beta-cell adaptation or dysfunction by comparing pancreatic islet gene expression profiles across multiple experimental animal models of diabetes. The goal of these studies is to identify new signaling pathways and targets for the development of therapeutic strategies to restore pancreatic beta-cell function in patients with diabetes.

References:

1. Thomas MK, Yao KM, Tenser MS, Wong GG, Habener JF. Bridge-1: A novel PDZ domain coactivator of E2A-mediated regulation of insulin gene transcription, Mol Cell Biol 1999;19:8492-04.

2. Thomas MK, Rastalsky N, Lee JH, Habener JF. Hedgehog signaling regulation of insulin production by pancreatic b-cells, Diabetes 2000;49:2039-2047.

3. Thomas MK, Lee JH, Rastalsky N, Habener JF. Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic b-cells, Endocrinology 2001;142:1033-1040.

4. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes, Diabetes 2001;50:521-533.

5. Thomas MK, Devon ON, Lee JH, Peter A, Schlosser DA, Tenser MS, Habener JF. Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1, J Clin Invest 2001;108:319-29.

6. Thomas MK. Use of stem cells to produce insulin-secreting islets. In Braunwald E, Fauci AS, Isselbacher KJ, Kasper DL, Hauser SL, Longo DL, Jameson JL. Harrison’s Online(www.harrisonsonline.com), Chapter 33 review editorial, 2001.

7. Thomas MK, Habener JF. Pancreas development. In: Gill RG, Harmon JT, MacLaren NK, eds. Immunologically Mediated Endocrine Disorders. Lippincott Williams and Williams 2002, p.141-166.

8. Thomas MK. Hedgehog signaling in pancreas development and the regulation of insulin production, Curr Opin Endocrinol Diabetes 2002;9:168-173.

9. Andreassen OA, Dedeoglu A, Stanojevic V, Hughes DB, Browne SE, Leech CA,Ferrante RJ, Habener JF, Beal MF, Thomas MK. Huntington’s disease of the endocrine pancreas: Insulin deficiency and diabetes mellitus due to impaired insulin gene expression, Neurobiol Dis 2002;11:410-424.

10. Kemp DM, Thomas, MK, Habener JF. Developmental aspects of the endocrine pancreas, Reviews in Endocrine and Metabolic Disorders 2003;4:5-17.

11. Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and Type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2004, p. 552-556.

12. Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 2004; 145: 2918-28.

13. Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology 2004(in press)


	Melissa Thomas, M.D., Ph.D. Transcriptional Regulation of Pancreatic Beta Cells The primary goal of the Thomas laboratory is to identify novel methods to restore pancreatic beta-cell function and insulin production in patients with diabetes. The major research focus is to define molecular mechanisms of pancreatic beta-cell dysfunction and adaptation in cellular and animal model systems. Dr. Thomas’ interest in mechanisms of transcriptional regulation is of clinical relevance in light of the strong association between mutations of pancreatic beta-cell transcription factors and heritable forms of diabetes in humans. Current research projects in the laboratory include the following: 1. Regulation of pancreatic beta-cell function by coactivators. Dr. Thomas and colleagues discovered a novel coactivator, designated Bridge-1, that regulates the transcriptional activation of the insulin promoter. The laboratory has identified several transcriptional regulatory proteins that interact with Bridge-1 and is studying the mechanism by which Bridge-1 regulates insulin production. Dr. Thomas has developed mouse models of Bridge-1 dysregulation and their pancreatic and metabolic phenotypes are under analysis. The laboratory also is collaborating with a human geneticist to look for mutations in the Bridge-1 gene in individuals with adult-onset diabetes. In collaboration with the Habener laboratory, Dr. Thomas is investigating the regulation of the MODY4 gene product PDX-1 by interactions with coactivators. The research team has identified mutations in PDX-1 that alter its interaction with the coactivator p300, providing a distinct mechanism by which mutations in the human pdx-1 gene can result in impaired insulin production and metabolic dysfunction. 2. Transcriptional regulation of adult pancreatic beta cells by morphogens A second series of studies in the laboratory is focused on the regulation of adult pancreatic beta-cell function by growth factors and morphogens that play essential roles in pancreas development, including hedgehog proteins. Dr. Thomas identified new functions for these signaling pathways in the transcriptional regulation of the insulin and pdx-1 genes that are essential for metabolic regulation in the adult. Dr. Thomas and colleagues are developing mouse models to elucidate mechanisms by which hedgehog signals regulate insulin production in the adult pancreas. In a collaborative project, studies of the regulation of insulin production by activin signaling via Smad transcription factors are ongoing. 3. Age-dependent changes in the transcriptional regulation of pancreatic beta cells. In a mouse model of inducible PDX-1 deficiency that Dr. Thomas developed, she discovered that younger but not older mice were able to compensate for the suppression of PDX-1 expression and maintain normal glucose homeostasis. In contrast older mice were susceptible to the suppression of PDX-1 expression and developed inducible hyperglycemia. She extended those studies to identify an inbred mouse strain in which younger mice were susceptible to the suppression of PDX-1 expression, suggesting that distinct heritable phenotypes exist that confer susceptibility to or compensation for PDX-1 deficiency. The laboratory is characterizing age-dependent beta-cell dysfunction in animal models with the goal of identifying changes in the transcriptional regulation of pancreatic beta cells that may confer a predisposition to the development of diabetes in older individuals. 4. Regulatory themes of adult pancreatic beta-cell adaptation and dysfunction. This exploratory collaborative project was designed to define regulatory themes of pancreatic beta-cell adaptation or dysfunction by comparing pancreatic islet gene expression profiles across multiple experimental animal models of diabetes. The goal of these studies is to identify new signaling pathways and targets for the development of therapeutic strategies to restore pancreatic beta-cell function in patients with diabetes. References: 1. Thomas MK, Yao KM, Tenser MS, Wong GG, Habener JF. Bridge-1: A novel PDZ domain coactivator of E2A-mediated regulation of insulin gene transcription, Mol Cell Biol 1999;19:8492-04. 2. Thomas MK, Rastalsky N, Lee JH, Habener JF. Hedgehog signaling regulation of insulin production by pancreatic b-cells, Diabetes 2000;49:2039-2047. 3. Thomas MK, Lee JH, Rastalsky N, Habener JF. Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic b-cells, Endocrinology 2001;142:1033-1040. 4. Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes, Diabetes 2001;50:521-533. 5. Thomas MK, Devon ON, Lee JH, Peter A, Schlosser DA, Tenser MS, Habener JF. Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1, J Clin Invest 2001;108:319-29. 6. Thomas MK. Use of stem cells to produce insulin-secreting islets. In Braunwald E, Fauci AS, Isselbacher KJ, Kasper DL, Hauser SL, Longo DL, Jameson JL. Harrison’s Online(www.harrisonsonline.com), Chapter 33 review editorial, 2001. 7. Thomas MK, Habener JF. Pancreas development. In: Gill RG, Harmon JT, MacLaren NK, eds. Immunologically Mediated Endocrine Disorders. Lippincott Williams and Williams 2002, p.141-166. 8. Thomas MK. Hedgehog signaling in pancreas development and the regulation of insulin production, Curr Opin Endocrinol Diabetes 2002;9:168-173. 9. Andreassen OA, Dedeoglu A, Stanojevic V, Hughes DB, Browne SE, Leech CA,Ferrante RJ, Habener JF, Beal MF, Thomas MK. Huntington’s disease of the endocrine pancreas: Insulin deficiency and diabetes mellitus due to impaired insulin gene expression, Neurobiol Dis 2002;11:410-424. 10. Kemp DM, Thomas, MK, Habener JF. Developmental aspects of the endocrine pancreas, Reviews in Endocrine and Metabolic Disorders 2003;4:5-17. 11. Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and Type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2004, p. 552-556. 12. Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 2004; 145: 2918-28. 13. Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology 2004(in press)