BADERC-David Rhoads

David Rhoads, Ph.D.

beta cell transcription factors Obesity & intestinal function

Our two research projects focus on the metabolic disorders of Type 2 diabetes and obesity. The ability to engineer tissues capable of regulated insulin secretion would be a major advance toward management of T2DM. The b-cell phenotype is established by its unique transcription factor network, maintained by multiple reciprocal interactions. We postulate that these interactions can be exploited to produce sustained expression of key b-cell transcription factors and ultimately the entire network. To this end, we have been dissecting the interactions of hepatocyte nuclear factors HNF1a, HNF1b, and HNF4a, prototypic for pancreatic islet lineage specification and essential for b cell differentiation and function. These TFs exhibit reciprocal induction (activate each other’s expression). Efforts are underway to incorporate these features into expression vectors for use in engineering non-b cells to perform regulated insulin secretion. We are also modifying native promoters to enhance their activities for use in these expression vectors. Our main goal is to achieve sustained transgene expression dependent on native promoters that recapitulate inherent regulation without reliance on potentially toxic constitutive or viral promoters.

Nutritional homeostasis is a complex interaction among hunger/satiety signals, nutrient intake/disposal, and the physiological responses of multiple tissues. Imbalances underlying obesity have been identified in each of these components. We have focused on the intestinal Na+/glucose cotransporter SGLT1 as a marker and potential etiological factor. SGLT1 is normally regulated with diurnal rhythmicity, but its expression is increased in T2DM and obesity. Studies are directed toward delineating the neuronal, hormonal, and luminal signaling pathways regulating SGLT1 and examining the impact of pharmacological or surgical strategies to modulate its expression. Ultimately, we hope to identify targets amenable to pharmaceutical control of carbohydrate absorption in conditions such as obesity and diabetes.

References:

Huang J, LL Levitsky, and DB Rhoads. Novel P2 promoter-derived HNF4a isoforms with different N-terminus generated by alternate exon insertion. Exp Cell Res 315: 1200-11, 2009.
Rhoads DB and LL Levitsky. The Function of HNF1 in the Pathogenesis of Diabetes. Expert Rev. Endocrinol. Metab. 3: 391-403, 2008.
Huang J, V Karakucuk, LL Levitsky, and DB Rhoads. Expression of HNF4a variants in pancreatic islets and Ins-1 b cells. Diabetes Metab Res Rev 24: 533-543, 2008.
Wang L, C Coffinier, MK Thomas, L Gresh, G Eddu, T Manor, LL Levitsky, M Yaniv, and DB Rhoads. Selective deletion of the Hnf1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology, 2004.
Stearns AT, A Balakrishnan, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Diurnal expression of the rat intestinal sodium-glucose cotransporter 1 (SGLT1) is independent of local luminal factors. Surgery 145: 294-302, 2009.
Stearns AT, A Balakrishnan, J Rounds, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na+/glucose cotransporter SGLT1. Am J Physiol Gastrointest Liver Physiol 294: G1078-83, 2008.
Balakrishnan A, AT Stearns, J Rounds, J Irani, M Giuffrida, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Diurnal rhythmicity in glucose uptake is mediated by temporal periodicity in the expression of the sodium-glucose cotransporter (SGLT1). Surgery 143: 813-8, 2008.
Balakrishnan A, AT Stearns, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing. Surgery 144: 168-73, 2008.
Tavakkolizadeh A, A Ramsanahie, LL Levitsky, MJ Zinner, EE Whang, SW Ashley, and DB Rhoads. Differential role of vagus nerve in maintaining diurnal gene expression rhythms in the proximal small intestine. J Surg Res 129: 73-8, 2005.
Tavakkolizadeh A, UV Berger, KR Shen, LL Levitsky, MJ Zinner, MA Hediger, SW Ashley, EE Whang, and DB Rhoads. Diurnal rhythmicity in intestinal SGLT-1 function, Vmax, and mRNA expression topography. Am J Physiol Gastrointest Liver Physiol 280: G209-15, 2001.
Rhoads DB, DH Rosenbaum, H Unsal, KJ Isselbacher, and LL Levitsky. Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is transcriptionally regulated. J Biol Chem 273: 9510-6, 1998.






			David Rhoads, Ph.D. beta cell transcription factors Obesity & intestinal function Our two research projects focus on the metabolic disorders of Type 2 diabetes and obesity. The ability to engineer tissues capable of regulated insulin secretion would be a major advance toward management of T2DM. The b-cell phenotype is established by its unique transcription factor network, maintained by multiple reciprocal interactions. We postulate that these interactions can be exploited to produce sustained expression of key b-cell transcription factors and ultimately the entire network. To this end, we have been dissecting the interactions of hepatocyte nuclear factors HNF1a, HNF1b, and HNF4a, prototypic for pancreatic islet lineage specification and essential for b cell differentiation and function. These TFs exhibit reciprocal induction (activate each other’s expression). Efforts are underway to incorporate these features into expression vectors for use in engineering non-b cells to perform regulated insulin secretion. We are also modifying native promoters to enhance their activities for use in these expression vectors. Our main goal is to achieve sustained transgene expression dependent on native promoters that recapitulate inherent regulation without reliance on potentially toxic constitutive or viral promoters. Nutritional homeostasis is a complex interaction among hunger/satiety signals, nutrient intake/disposal, and the physiological responses of multiple tissues. Imbalances underlying obesity have been identified in each of these components. We have focused on the intestinal Na+/glucose cotransporter SGLT1 as a marker and potential etiological factor. SGLT1 is normally regulated with diurnal rhythmicity, but its expression is increased in T2DM and obesity. Studies are directed toward delineating the neuronal, hormonal, and luminal signaling pathways regulating SGLT1 and examining the impact of pharmacological or surgical strategies to modulate its expression. Ultimately, we hope to identify targets amenable to pharmaceutical control of carbohydrate absorption in conditions such as obesity and diabetes. References: Huang J, LL Levitsky, and DB Rhoads. Novel P2 promoter-derived HNF4a isoforms with different N-terminus generated by alternate exon insertion. Exp Cell Res 315: 1200-11, 2009. Rhoads DB and LL Levitsky. The Function of HNF1 in the Pathogenesis of Diabetes. Expert Rev. Endocrinol. Metab. 3: 391-403, 2008. Huang J, V Karakucuk, LL Levitsky, and DB Rhoads. Expression of HNF4a variants in pancreatic islets and Ins-1 b cells. Diabetes Metab Res Rev 24: 533-543, 2008. Wang L, C Coffinier, MK Thomas, L Gresh, G Eddu, T Manor, LL Levitsky, M Yaniv, and DB Rhoads. Selective deletion of the Hnf1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology, 2004. Stearns AT, A Balakrishnan, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Diurnal expression of the rat intestinal sodium-glucose cotransporter 1 (SGLT1) is independent of local luminal factors. Surgery 145: 294-302, 2009. Stearns AT, A Balakrishnan, J Rounds, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na+/glucose cotransporter SGLT1. Am J Physiol Gastrointest Liver Physiol 294: G1078-83, 2008. Balakrishnan A, AT Stearns, J Rounds, J Irani, M Giuffrida, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Diurnal rhythmicity in glucose uptake is mediated by temporal periodicity in the expression of the sodium-glucose cotransporter (SGLT1). Surgery 143: 813-8, 2008. Balakrishnan A, AT Stearns, DB Rhoads, SW Ashley, and A Tavakkolizadeh. Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing. Surgery 144: 168-73, 2008. Tavakkolizadeh A, A Ramsanahie, LL Levitsky, MJ Zinner, EE Whang, SW Ashley, and DB Rhoads. Differential role of vagus nerve in maintaining diurnal gene expression rhythms in the proximal small intestine. J Surg Res 129: 73-8, 2005. Tavakkolizadeh A, UV Berger, KR Shen, LL Levitsky, MJ Zinner, MA Hediger, SW Ashley, EE Whang, and DB Rhoads. Diurnal rhythmicity in intestinal SGLT-1 function, Vmax, and mRNA expression topography. Am J Physiol Gastrointest Liver Physiol 280: G209-15, 2001. Rhoads DB, DH Rosenbaum, H Unsal, KJ Isselbacher, and LL Levitsky. Circadian periodicity of intestinal Na+/glucose cotransporter 1 mRNA levels is transcriptionally regulated. J Biol Chem 273: 9510-6, 1998.