Molecular Genetics

Research Activities

Molecular Genetic Analysis of Obesity and Diabetes We continue to pursue research regarding the molecular genetics of obesity in humans (R01 DK52431-13) with increased emphasis on computational analysis of gene by gene interactions and common genetic variants in FTO/FTM that are associated with obesity. A second project (R01 DK66518-03) is designed to clone modifier genes for type 2 diabetes from obese mice. We have identified a candidate gene of unknown function whose hypoactivity causes reduced beta cell mass. The molecular physiology of this gene is being pursued in knockout mice. (NIH/NIDDK R01 DK52431-15, R01 DK66518-06)

Experimental Weight Perturbation in Humans
Dr. Michael Rosenbaum leads the investigation and clinical research on the complex metabolic responses associated with weight loss. We are continuing to investigate the molecular physiology of responses to weight perturbation in humans, focusing on the role of leptin in these responses. (NIH/NIDDK R01 DK64773-06)

Diabetes & Endocrinology Research Center.
Genomics Core Director and Co-Director of DERC (Leibel)
The major goal of this Center is to promote interactions among research groups in diabetes, obesity, lipid metabolism, structural biology, immunology and beta cell transplantation through the Naomi Berrie Diabetes Center at Columbia University. (NIH/NIDDK P30 DK63068-06)

Leptin Biology of Adipose Tissue
The laboratory of Dr. Yiying Zhang's lab in the past year has investigated the physiological role of peripheral leptin receptor in regulating leptin axis and local and systemic energy and metabolism. She has shown that peripheral leptin receptor/signaling is an important regulator of leptin production, clearance and bioactivity, but has little impact on local or systemic energy metabolism.

Dr. Zhang has also investigated the molecular mechanisms by which leptin gene expression in adipocytes is regulated to closely reflect changes in adipocyte size and acute energy balance. She demonstrated that blocking glucose uptake or metabolism by pharmacological inhibitors abolishes or diminishes the correlation between leptin mRNA levels and cell size in isolated adipocytes, suggesting that metabolism is an underlying force that determines the relationship between leptin gene expression and adipocyte size. (NIH/NIDDK R01 DK63034-04)

Clinical

• Genetic Basis of Cardiac Disease
  As the molecular genetics core laboratory for the Pediatric Heart Network, under the leadership of Dr. Chung, we are identifying genetic factors modulating disease severity associated with congenital heart disease. We are characterizing the frequency and types of mutations associated with cardiomyopathy, arrhythmias, and pulmonary hypertension and genes that modify their penetrance. We are also clinically and genomically characterizing children with congenital heart disease for copy number changes.

• Pediatric Neuromuscular Clinical Research Network
  As the molecular genetics core for the Pediatric Neuromuscular Clinical Research Network, under the leadership of Dr. Chung, the goal of this project is to establish a clinical research network that clinically and molecularly characterizes patients with spinal muscular atrophy at baseline and establishes biomarkers to monitor clinical efficacy in preparation for SMA clinical trials.

• Identification of a Novel Breast Cancer Susceptibility Gene in the Ashkenazi Jewish Population (Fuirst Foundation, Manhasset Women's Coalition Against Breast Cancer)
  We are identifying novel genes for breast cancer susceptibility through the Breast Cancer Family Registry. The goal of this project is to initially map and then clone a novel gene for breast cancer susceptibility by testing in Ashkenazi Jewish families with hereditary breast cancer who do not harbor mutations in BRCA1 or BRCA2. Dr. Chung is also a co-investigator of the Breast Cancer Family Registry.

• PET Imaging of Beta Cells in Humans (NIH/NIDDK R01 DK77493-02)
  We are collaborating with Paul E. Harris, PhD, and Robin Goland, MD (Dept. of Medicine) on PET imaging of human beta cells. PET scans will be used to visualize beta cells of the pancreas. The ability to do so will be enormously helpful in following the natural history of both type 1 and type 2 diabetes, and in helping in the design and evaluation of new drugs. Preliminary studies have been promising and an R01 grant application has been submitted to continue funding of this research.

• Risk factors for type 2 diabetes mellitus in children
  This project examines the prevalence of pre-diabetic risk factors in children in mid-puberty.

• Prevention of type 2 diabetes mellitus in children
  This project examines the prevalence of pre-diabetic risk factors and the response of these risk factors to a predominantly Latino New York City Public Junior High School-based exercise, health, and nutrition education plan. Funds are shared with Maimonides Medical Center who expanding these studies to include African-American students.

• Diabetes Risk Factors and school based intervention
  This project expands our analyses of diabetes risk factors and their response to a school-based intervention. This is a 5-site study (CUMC, Maimonides, Long Island Jewish Medical Center, Mt. Sinai Medical Center, and Winthrop Hospital) covering multiple ethnic groups (Latino, African-American, Asian-American, and Caucasian-American) and multiple age groups (10-15) years. Results are coupled to ongoing genetic studies of candidate diabetes susceptibility genes.

• Ontogeny of the hypothalamic feeding circuitry
  The goal of this study is to begin a project to identify novel molecular markers for orexigenic and anorexigenic neuronal populations in the hypothalamic circuits that regulate feeding and energy expenditure.