Lawrence Chan, M.B., B.S., D.Sc.
Professor of Molecular and Human Genetics
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, and 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.
- Yang Y, Chang BH, Chan L (2013). Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults. EMBO Mol. Med. 5(1): 92-104. PubMed PMID: 23197416
- Chen W, Chang B, Saha P, Hartig SM, Li L, Reddy VT, Yang Y, Yechoor V, Mancini MA, Chan L (2012). Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Mol. Cell Biol. 32(6): 1099-111. PubMed PMID: 22269949
- Poungvarin N, Lee JK, Yechoor VK, Li MV, Assavapokee T, Suksaranjit P, Thepsongwajja JJ, Saha PK, Oka K, Chan L (2012). Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity. Diabetologia 55(6): 1783-96. PubMed PMID: 22382520
- Terashima T, Kojima H, Chan L (2012). Bone marrow expression of poly(ADP-ribose)polymerase underlies diabetic neuropathy via hematopoietic-neuronal cell fusion. FASEB J. 26(1): 295-308. PubMed PMID: 21978940
- Yang Y, Chang BH, Yechoor V, Chen W, Li L, Tsai MJ, Chan L (2011). The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice. Diabetologia 54(10): 2595-605. PubMed PMID: 21786021
- Saha PK, Reddy VT, Konopleva M, Andreeff M, Chan L (2010). The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. J. Biol. Chem. 285(52): 40581-92. PubMed PMID: 20956520
- Chen W, Chang B, Li L, Chan L (2010). Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 52(3): 1134-42. PubMed PMID: 20648554
- 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. Dev. Cell 16(3): 358-373. PubMed PMID: 19289082
- 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(11): 4863-4873. PubMed PMID: 19819964
- Samson SL, Gonzalez EV, Yechoor V, Bajaj M, Oka K, Chan L (2008). Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. Mol. Ther. 16(11): 1805-12. PubMed PMID: 18781141
Lawrence Chan, M.B., B.S., D.Sc.
Department of Medicine-Endocrinology
Baylor College of Medicine
One Baylor Plaza, BCM185
Houston, TX, 77030, U.S.A.