Lawrence C. B. Chan, M.D., D.Sc
Betty Rutherford Chair for Diabetes Research
Department of Medicine
Department of Molecular and Cellular Biology
Chief, Division of Diabetes, Endocrinology and Metabolism
- M.B., B.S.; D.Sc., University of Hong Kong
- Postdoctoral, Washington University, St. Louis
Dr. Chan's laboratory is active in the following research areas: (1) type 1 and type 2 diabetes and the metabolic syndrome, (2) lipoprotein metabolism and atherosclerosis, and (3) 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 hyperglycemic states, resulting from type 1 and type 2 diabetes or simply glucose injection-induced hyperglycemia. The laboratory showed that the insulin-producing cells are derived from bone marrow cells, which are induced to express multiple islet hormones in response to elevated blood glucose. These cells 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, possibly mediating some of the chronic diabetic complications. His laboratory is investigating the possible role of these peripheral insulin-producing cells in the modulation of autoimmune (type 1) diabetes, and as a causative factor of different chronic diabetic complications.
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, NeuroD (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.
In the area of metabolic syndrome and type 2 diabetes, the Chan laboratory is investigating the role of different fat cell-specific proteins in carbohydrate and lipid homeostasis. They produced mutant mice, including those with inactivated perilipin and adipocyte differentiation related protein (ADRP), to dissect the various biochemical pathways that regulate lipolysis and energy metabolism in vivo. For example, they found that perilipin-null mice are lean and resistant to diet-induced and genetic obesity, and that the absence of perilipin activates a number of biochemical pathways that enable these animals to efficiently burn the extra fat and stay lean.
The Chan laboratory has been active in the lipoprotein/atherosclerosis area for over twenty-five years. He and his coworkers first cloned the vertebrate apolipoprotein genes, developed the now widely accepted apolipoprotein multigene family concept, and discovered apolipoprotein B mRNA editing. They cloned the different vascular lipase genes and were among the first to describe the molecular genetics and the specific mutations in families with type 1 hyperlipoproteinemia. They recently showed that mice with inactivate endothelial lipase have elevated high density lipoprotein (HDL), defining an important role for this newly described vascular lipase. They also found an association between a single nucleotide polymorphism in the endothelial lipase gene and plasma HDL cholesterol concentration in humans. Using various mouse mutants, the Chan laboratory dissected the molecular pathology of atherosclerosis development. It determined the role of different cell cycle-related molecules, such as p53 and p21, in atherosclerosis, providing mechanistic insight into the diverse actions of these proteins on apoptosis, cellular proliferation, and inflammation, in the context of atherosclerosis. His laboratory also produced the initial evidence that C-reactive protein (CRP) is a pro-atherogenic molecule in mice in vivo, indicting that CRP is not simply a clinical marker, but an active player, in atherosclerosis.
In the area of molecular therapy, Dr. Chan's laboratory has been developing gene therapy regimens that not only inhibit atherosclerosis development, but also remodel atheromatous plaques, changing them from vulnerable to stable-looking lesions. In collaboration with the Department of Molecular and Human Genetics, Dr. Chan has been in the forefront of adenviral vector application and development. Use of the helper-dependent adenovirus developed by this collaboration leads to stable long-term transgene expression and life-time reversal of genetic hyperlipidemia in mice.
Metabolic syndrome is a major cause of type 2 diabetes, and obesity is a dominant pathological factor in the process. 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.
- Ma K, Cilingiroglu M, Otvos JD, Ballantyne CM, Marian AJ, and Chan L (2003) Endothelial lipase is a major genetic determinant for high density lipoprotein concentraton, structure and metabolism. Proc Natl Acad Sci USA 100:2748-2753.
- Belalcazar LM, Merched A, Carr B, Oka K, Chen KH, Pastore L, Beaudet AB, and Chan L (2003) Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Circulation 107:2726-2732.
- Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, and Chan L (2003) NeuroD/Betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nature Medicine 9:596-603.
- Merched A, Williams E, Chan L (2003) Macrophage-specific p53 expression plays a crucial role in atherosclerosis development and plaque remodeling. Arterio Thromb Vasc Biol 23: 1608-1614.
- Castro-Chavez F, Yechoor VK, Saha PK, Martinez-Botas J, Wooten EC, O'Connell P, Taegtmeyer H, Chan L (2003) Coordinated up-regulation of oxidative pathways and down-regulation of lipid biosynthesis underlie obesity resistance in perilipin knockout mice: a microarray gene expression profile. Diabetes 52:2666-2674.
- Lau PP, Chan L (2003) Involvement of a chaperone regulator, Bcl2-associated Athanogene-4 (BAG-4), in apolipoprotein B mRNA editing. J Biol Chem 278:52988-52996.
- Paul A, Kerry WS, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L (2004) C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 109: 647-655.
- Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, and Chan L (2004) Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc Natl Acad Sci USA 101:2458-2463.
- Saha P, Kojima H, Martinez-Botas J, Sunehag AL, Chan L (2004) Metabolic adaptations in the absence of perilipin: Increased -oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice. J Biol Chem 279:35150-35158.
- Nomura S, Merched A, Nour E, Dieker C, Oka K, Chan L (2004) Low density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia. Gene Therapy 11:1540-1548.
- Kolonin MG, Saha PK, Chan L, Pasqualini R Arap W (2004) Reversal of obesity by targeted ablation of adipose tissue. Nature Medicine 10: 625-632.
- Merched AJ, Chan L (2004) Absence of p21Waf1/Cip1/Sdi1 modulates macrophage differentiation and inflammatory response and protects against atherosclerosis. Circulation 110:3830-3841.
- Ma K, Forte T, Otvos JD, Chan L (2005) Differential, additive effects of endothelial lipase and scavenger receptor-class B type 1 on HDL metabolism in knockout mouse models. Arterio Thromb Vasc Biol 25:149-154.
- Terashima T, Kojima H, Fujimiya M, Matsumura K, Oi J, Hara M, Kashiwagi A, Kimura H, Yasuda H, Chan L (2005) The fusion of bone marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy. Proc Natl Acad Sci USA 102: 12525-12530.
- Chang BH-J, Li L, Paul A, Taniguchi S, Nannegari V, Heird WC, Chan L (2006) Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation related protein (ADFP). Mol Cell Biol 26:1063-1076.
- Samson SL, Chan L (2006) Gene therapy for diabetes: re-inventing the islet. Trends Endo Metab 17: 92-100.
- Li MV, Chang B, Imamura M, Poungvarin N, Chan L (2006) Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module. Diabetes 55:1179-1189.
- Oka K, Belalcazar LM, Dieker C, Nour EA, Nuno-Gonzalez P, Paul A, Cormier S, Shin J-K, Finegold M, Chan L (2007) Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. Gene Therapy 14: 191-202.
- Chang BH, Chan L (2007) Emerging role of lipid droplet protein ADFP in health and disease. Am J Physiol Gastroinest Liver Physiol 292: G1465-1468.
- Fujimiya M, Kojima H, Ichinose M, Arai R, Kimura H, Kashiwagi A, Chan L (2007) Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes. Proc Natl Acad Sci USA 104: 4030-4035.
- Matsumura K*, Chang BHJ*, Fujimiya M, Chen W, Kulkarni RN, Eguchi Y, Kimura H, Kojima H, Chan L (2007) Aquaporin 7 is a β cell protein and regulator of intraislet glycerol content and glycerol kinase activity, β cell mass, and insulin production and secretion. Mol Cell Biol 17: 6026-2037.
- Koeberl DD, Sun B, Bird A, Chen YT, Oka K, Chan L (2007) Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia. Molecular Therapy 15:1253-1258.