Circadian rhythms have recently become recognized as modulators of a wide array of physiological and pathological processes, including glucose homeostasis, exercise endurance, blood pressure and tumorigenesis. The long-term goal of the candidate is to develop novel therapeutic approaches for metabolic disease by continuing to investigate the interrelationship between circadian rhythms and cellular and organismal metabolism. An underlying hypothesis of this proposal is that metabolic physiology can be modulated at the transcriptional level by nutrient-sensing circadian repressors regulating nuclear hormone receptor (NR) function;advancing our functional understanding of these receptor and repressor interactions may highlight new therapeutic strategies for treating metabolic disease. The circadian clock components cryptochromes (Cry1 and Cry2) are nutrient-responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK), which causes their proteasomal degradation. Preliminary studies indicate that cryptochromes interact with and repress several nuclear hormone receptors, making them novel nutrient-responsive nuclear receptor corepressors. Nuclear hormone receptors are widely studied as critical regulators of several aspects of metabolic physiology. Biochemical, genetic, molecular and physiological approaches will be used to uncover the roles of Cry1 and Cry2 in nuclear hormone receptor pathways governing the control of glucose homeostasis and exercise physiology, in the following specific aims:
Aim I, characterize the roles of Cry1 and Cry2 in nuclear hormone receptor-dependent transcription (analysis of the physical and functional associations between Cry1 and Cry2 and mammalian nuclear hormone receptors);
Aim 2, examine the roles of Cry1 and Cry2 in glucose homeostasis (characterization of glucose regulation in Cry-deficient mice before and after hormone treatment;examination of hormone-dependent gene regulation in livers);
Aim 3, examine the roles of Cry1 and Cry2 in exercise physiology (characterize muscle biology, physiology and exercise endurance in Cry-deficient mice;examine gene expression in muscles before and after pharmacological treatments).

Public Health Relevance

Diabetes and the metabolic syndrome are growing public health concerns in the United States. Nuclear hormone receptors govern a wide array of metabolic physiological processes, the disruption of which contributes to metabolic disorders. This project involves the study of a novel regulator for nuclear hormone receptor function and will contribute to the knowledge base needed for the development of therapeutic strategies to treat metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK090188-02
Application #
8215772
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$148,500
Indirect Cost
$11,000
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jordan, Sabine D; Lamia, Katja A (2013) AMPK at the crossroads of circadian clocks and metabolism. Mol Cell Endocrinol 366:163-9
Lamia, Katja A; Papp, Stephanie J; Yu, Ruth T et al. (2011) Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480:552-6