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diabetes-endocrinology

Houston, Texas

Anatomy instruction at Baylor College of Medicine
Medicine/Endocrinology
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Lawrence C. B. Chan, M.D., D.Sc

Dr. Lawrence ChanBetty Rutherford Chair for Diabetes Research
Professor of Medicine and Molecular & Cellular Biology
Chief, Division of Diabetes, Endocrinology & Metabolism
Director, Diabetes & Endocrinology Research Center

Contact Information

One Baylor Plaza, Room R614
Houston, TX 77030
Tel: 713-798-4478
Fax: 713-798-8764
E-mail: lchan@bcm.edu

Dr. Lawrence Chan is the Betty Rutherford Chair for Diabetes Research and and the Director of the NIH-funded Diabetes & Endocrinology Research Center at Baylor College of Medicine. He is also the director of the Molecular Medicine Scholars Program and a professor in the departments of Medicine and Molecular and Cellular Biology.

He is recognized as a preeminent investigator in the development of novel therapies in Diabetes, and an authority in the genetics of atherosclerosis and lipid disorders. Dr. Chan was the recipient of a MERIT Award from the National Institutes of Health and is principal investigator of multiple NIH grants. He has received numerous national and international honors and awards from organizations including the American Diabetes Association, the Endocrine Society, the American Heart Assocition and the Juvenile Diabetes Research Association. He is also an elected member of the American Society for Clinical Investigation and the Association of American Physicians.

Education

M.B., B.S.; D.Sc.: University of Hong Kong
Postdoctoral: Washington University, St. Louis

Research Interests

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.

Publications

  1. 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.
  2. Chang BH, Chan L (2007) Emerging role of lipid droplet protein ADFP in health and disease.Am J Physiol Gastroinest Liver Physiol [Dec 28, 2006; Epub ahead of print]
  3. 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.
  4. Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, Sweeney JF, Peterson LE, Chan L, Smith CW, Ballantyne CM (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115: 1029-1038.
  5. Tao L, Gao E, Jiao X, Yuan Y, Li S, Christopher TA, Lopez BL, Koch W, Chan L, Goldstein BJ, Ma XL (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115 (Epub ahead of print)
  6. 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.
  7. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116: 1102-1109.
  8. 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.
  9. Wang Y, Lam KSL, Chan L, Chan KW, Lam JBB, Lam MC, Hoo RCL, Mak WWN, Cooper GJS, Xu A (2006) Posttranslational modifications on the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high-molecular-weight oligomeric complex. J Biol Chem 281: 16391-16400.
  10. Sun Y, Asnicar M, Saha PK, Chan L, Smith RG (2006) Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab 3: 379-386.
  11. MacDougall ED, Kramer F, Polinsky P, Barnhart S, Varon R, Rosenfeld ME, Oka K, Chan L, Schwartz SM, Bornfeldt KE (2006) Aggressive VLDL and LDL lowering by gene transfer of the VLDL receptor combined with a low fat diet regimen induces regression and reduces macrophage content in advanced atherosclerotic lesions in LDL receptor-deficient Mice. Am J Path 168: 2064-2073.
  12. 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. Sept. 30.
  13. 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.
  14. Schillinger KJ, Tsai SY, Taffet GE, Reddy AK, Marian AJ, Entman ML, Oka K, Chan L, O'Malley BW (2005) Regulatable atrial natriuretic peptide gene therapy for hypertension. Proc Natl Acad Sci USA 102: 13789-13794.
  15. Ko KW, Paul A, Ma K, Li L, Chan L (2005) Endothelial lipase modulates plasma lipoprotein profiles but has no effect on the development of atherosclerosis in apoE-/- and LDLR-/- mice, J Lipid Res, E-pub
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Merched AJ, Chan L (2004) Absence of p21Waf1/Cip1/Sdi1 modulates macrophage differentiation and inflammatory response and protects against atherosclerosis. Circulation 110:3830-3841.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.

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