Molecular Genetics

Research Activities

Molecular Genetic Analysis of Obesity and Diabetes (NIH/NIDDK R01 DK52431-13, R01 DK66518-03)
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. As part of the project we recently created a mouse carrying a human gene variant in the leptin receptor that has been associated with excess body fat. We are studying the ingestive behavior and energy expenditure of this mouse. 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.

Experimental Weight Perturbation in Humans (NIH/NIDDK R01 DK64773-04)
We are continuing to investigate the molecular physiology of responses to weight perturbation in humans, focusing on the role of leptin in these responses. Dr. Michael Rosenbaum leads the investigation and clinical research on the complex metabolic responses associated with weight loss. A competitive renewal of the NIH R01 grant which supports this work has been submitted.

Leptin Biology of Adipose Tissue (NIH/NIDDK R01 DK63034-04)
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 1) direct leptin signaling regulate leptin protein production at a post-transcriptional level; 2) soluble leptin receptor produced in peripheral tissues regulates leptin clearance and bioactivity; 3) adipocyte expression of beta3-AR, a major regulator of adipocyte lipolysis, is regulated by central leptin signaling, not adipocyte leptin signaling; 4). direct leptin signaling in adipocytes does not have long term, cell-autonomous effects on the rate of lipid accumulation in vivo. Together, these data suggest 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 examined the relationship between adipocyte size, glucose metabolism and leptin mRNA levels, and found 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.

Pediatric Heart Network
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 and rate of progression for cardiomyopathy and pulmonary hypertension. We are also clinically and genomically characterizing children with congenital heart disease for copy number changes. The goal of this project is to serve as the genetics core for the multi-site pediatric heart network that was established to study cardiac disease unique to children. The genetics core will bank DNA samples on all study participants and perform genotypic analysis relevant to the clinical studies.

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 methods of monitoring 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.

PET Imaging of Beta Cells in Humans (NIH/NIDDK P30 DK63608-04, R01 pending)
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.