Grant: $50,000 - Department of Health and Human Services - Sep. 21, 2009
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Award Description: We will continue studies of the role of CEACAM1 in insulin metabolism. CEACAM1 is a substrate of the insulin receptor kinase in the liver. In the first four years of funding, we have demonstrated that hepatic CEACAM1 plays a pivotal role in the formation of the insulin-receptor endocytosis complex to promote insulin uptake and degradation, an event that constitutes the basic mechanism of insulin clearance in liver. Using transgenic mice expressing a dominant-negative mutant CEACAM1, we have shown that functional inactivation of CEACAM1 in liver impairs insulin clearance and results in hyperinsulinemia, altered lipid metabolism and increased visceral adiposity. We propose to investigate the pathogenesis of the metabolic syndrome caused by altered CEACAM1 function using Ceacam1-deficient (Cc1-/-) mice. In contrast to the human genome, which harbors a single Ceacam gene, the mouse genome harbors two genes (Cc1 and Cc2), differing in the tissue distribution of their protein products, with CEACAM1 being the predominant liver isoform and CEACAM2 being the predominant isoform in kidney and pancreatic b-cells. We present preliminary data showing that individual Cc1/- and Cc2-/- knockouts develop metabolic abnormalities with apparently different mechanisms. Cc1-/- null mice develop impaired insulin clearance and insulin resistance without diabetes, while Cc2-/- develop diabetes with impaired insulin secretion. We also show decreased hepatic CEACAM1 expression in other models of obesity and diabetes in rodents and in mice on a high-fat diet. Based on these observations, in Aim 1 we will investigate whether the mechanism of insulin resistance in Cc1-/- mice is due to impaired insulin clearance. In Aim 2, we will determine whether restoring CEACAM1 expression reverses the metabolic abnormalities of obese rodents. In Aim 3, we will investigate the mechanism of b-cells dysfunction in Cc2-/- knockouts, and whether restoring CEACAM2 expression in pancreatic b-cells rescues the diabetic phenotype of Cc2-/- mice. In Aim 4, we will study whether the two genes play overlapping or distinct functions by generating mice lacking both isoforms (Cc1-/-/Cc2-/-). The proposed studies should delineate a novel mechanism of insulin-resistant diabetes, one that highlights the role of insulin metabolism in regulating insulin sensitivity distinctly from insulin signaling.
Project Description: During the incoming quarter, we plan to generate a sufficient number of age-matched mice to carry out the outlined experiments. In parallel, we will also perform ovariectomy in Cc2–/– female mice and carry out the pair-feeding experiments in order to investigate whether hyperphagia is responsible for insulin resistance in these mice.
Jobs Summary: TECHNICAL JOBS (2): Retaining two technical associates, Mats Fernstrom and Jennifer Kalisz, who are instrumental in boosting our productivity and pace of discovery. FACULTY ASSISTANT JOBS (1): Dr. Tamara Castaneda is a junior Research Assistant Professor. Without this supplement, she would have been fired in 90 days. FACULTY JOBS (1): Dr. Sonia Najjar, Principal Investigator of this proposal, is required to cover 52% of her salary in order to remain active in research and maintain an open laboratory that provides a home for 8 gradaute students to pursue their PhD degrees and for technical personnel. Dr. Najjar is also Director of the Center for Diabetes and Endocrine Research. Her laboratory provides core work for other laboratories in the center. Because Dr. Najjar maintains 12 genetically modified mouse models of diabetes, which requires full-time veterinary care, this ARRA funding has promoted the need to retain 6 employees in the institutional Department of Laboratory Animal Medicine facility. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 21, 2009. Help expand these official descriptions using the wiki below.