Lawrence Chan, M.B., B.S., D.Sc.
Departments of Molecular and Cellular Biology and Medicine
M.B., B.S., D.Sc.: University of Hong Kong, Hong Kong, China
Postdoctoral training: Washington University, St. Louis
Diabetes, Gene Therapy, Insulin Resistance, Atherosclerosis, Lipoprotein Metabolism, Obesity
Dr. Chan's laboratory is active in the following research areas:
• Type 1 and type 2 diabetes and the metabolic syndrome, molecular biology and pathogenesis
• Somatic gene therapy and other molecular therapies for the treatment of diabetes and obesity
Dr. Chan is interested in the molecular pathology of hyperglycemia and diabetic complications. Dr. Chan and his colleagues first described the appearance of insulin-producing cells in multiple extrapancreatic tissues in diabetes. The laboratory showed that the insulin-producing cells are derived from bone marrow cells that migrate from the bone marrow to multiple tissues, including the liver and adipose tissues. They may retain their bone marrow cell characteristics or they may fuse with the local cells in various tissues and organs. His laboratory further showed that the fusion of these abnormal bone marrow-derived cells with nerve cells is an important factor in diabetic neuropathy.
Dr. Chan developed a novel therapy for a type 1 diabetes model in mice. He showed that gene therapy-mediated delivery of a transcription factor, Neurog3 (together with an islet growth factor, betacelluln) to the liver of diabetic mice leads to the development of new islets in the liver. These islets produce insulin and other islet hormones, leading to complete correction of the diabetes. The gene therapy-induced islet neogenesis strategy that "cures" type 1 diabetes in mice is significant, not only for its potential as a new treatment, but also because it is the first time a single transcription factor has been shown to lead to the biogenesis of a complete organ (endocrine pancreas) in an adult animal. His laboratory showed that the newly formed β cells were derived from adult stem cells in the liver by a process consistent with transdetermination.
Glis3 is a krüppel-like zinc finger transcription factor that is expressed in essentially all cells in the body. The factor is expressed at high levels in pancreatic β cells. Genome wide association studies among adult populations have found a strong association of Glis3 polymorphisms in type 1 and type 2 diabetes. Intriguingly, mutations in Glis3 have been reported to cause a syndrome of neonatal diabetes. The Chan laboratory is interested in the developmental biology of the endocrine pancreas, particularly in the molecular pathology of the neonatal diabetes syndrome. They found that Glis3 regulates pancreatic islet growth and differentiation during fetal development in mice. Moreover, they showed that Glis3 is required for normal insulin gene expression; importantly, it is indispensable for normal β cell function and β cell mass maintenance in adult animals. His group is pursuing the molecular characterization of the action of Glis3 in pancreatic β cell biology and function.
In the area of metabolic syndrome and type 2 diabetes, the Chan laboratory is investigating the role of different fat cell proteins in carbohydrate and lipid homeostasis. They produced mutant mice, including those with inactivated perilipin and adipocyte differentiation related protein (ADRP), as well as the gene for multiple other lipid droplet proteins, to dissect the biochemical pathways that regulate lipolysis and energy metabolism in vivo. He is interested in the role of the lipid droplet proteins in the molecular pathogenesis of lipodystrophy and type 2 diabetes. In collaboration with investigators at MD Anderson Cancer Center, the Chan laboratory used a fat vasculature homing peptide to deliver a pro-apoptotic gene, leading to targeted ablation of adipose tissue and reversal of obesity and diabetes in mice. The laboratory is investigating the use of this "molecular liposuction" as a possible approach to the treatment of obesity in nonhuman primates.
Baylor College of Medicine
One Baylor Plaza, R614
Houston, TX 77030
- Chang BH, Li L, Saha P, Chan L. (2010). Absence of adipose differentiation related protein upregulates hepatic VLDL secretion, relieves hepatosteatosis and improves whole body insulin resistance in leptin-deficient mice J Lipid Res 51: 2132-2142.
- Terashima T, Oka K, Kritz AB, Kojima H, Baker A, Chan L. (2009). DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice. J Clin Invest 119: 2100-2112. PMID: 19603551
- Yang Y, Chang B, Samson S, Li M, Chan L. (2009). The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription. Nucl Acids Res 37: 2529-2538.
- Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H, Chan L. (2009). Neurogenin3 is sufficient for in vivo transdetermination of hepatic progenitors cells into islet-like structures but not transdifferentiation of hepatocytes. Developmental Cell 16: 358-373.
- Yechoor V, Liu V, Paul A, Lee J, Buras E, Ozer K, Samson S, Chan L. (2009). Gene therapy with Neurogenin3 and betacellulin reverses major metabolic problems in insulin-deficient diabetic mice. Endocrinology 150: 4863-4873.
- Paul A, Chang BH-J, Li L, Yechoor V and Chan L. (2008). Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis. Circ Res 102:1492-1501.
- Merched AJ, Ko K, Gotlinger KH, Serhan CN and Chan L. (2008). Atherosclerosis: Evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J 22: 3595-3606.
- Matsumura K*, Chang BHJ*, Fujimiya M, Chen W, Kulkarni RN, Eguchi Y, Kimura H, Kojima H and Chan L. (2007). Aquaporin 7 is a ß cell protein and regulator of intra-islet glycerol content and glycerol kinase activity, ß cell mass, and insulin production and secretion. Mol Cell Biol 17: 6026-2037. * These authors contributed equally to this study.
- Koeberl DD, Sun B, Bird A, Chen YT, Oka K and Chan L. (2007). Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia. Molecular Therapy 15:1253-1258.
- Fujimiya M, Kojima H, Ichinose M, Arai R, Kimura H, Kashiwagi A and Chan L. (2007). Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes. Proc Natl Acad Sci USA 104:4030-4035.