Aldosterone is the major mineralocorticoid hormone that regulates sodium (Na) homeostasis and its action contributes to the maintenance of blood pressure and cardiac function. Abnormal aldosterone signaling can lead to hypertension, a syndrome that affects at least 25% of American adults. Hypertension is a primary risk factor for cardiovascular disease, the leading cause of death in the United States. Most known monogenetic causes of hypertension are due to a defect in the downstream targets of aldosterone action. The mechanism of aldosterone action is largely transcriptional with most known gene targets converging on the renal epithelial sodium channel (ENaC). Recent data suggest a role for the aldosterone target Period 1, a circadian rhythm gene, in mediating the aldosterone-dependent and independent regulation of the alpha subunit of ENaC ((ENaC), the rate limiting subunit for the Na channel in the kidney. Many physiological processes exhibit a circadian pattern, including the sleep-wake cycle, heart beat, hormone secretion, renal blood flow, and blood pressure. However, the role of the circadian clock in the regulation of these processes is not understood at a molecular level. The long term goal of these studies is to characterize the role of the circadian clock in hypertension and cardiovascular disease. The goal of the present application is to define a functional role for Per1 in the regulation of (ENaC. To this end, the aims of this proposal are to (1) characterize the Per1-mediated transcriptional regulation of the (ENaC gene, (2) define the role of Per1 in the regulation of ENaC activity, and (3) evaluate the role of Per1 in the regulation of (ENaC in vivo. Evidence of a direct molecular and physiological link between ENaC and the circadian clock is likely to have profound implications for understanding renal Na handling and possibly blood pressure control in pathophysiological conditions. The candidate will use the work described in this proposal as the basis for developing an independent line of research into circadian and aldosterone-mediated control of Na transport in the kidney. Thus, a comprehensive training program has been designed to move the applicant to a career as an independent investigator. Didactic coursework, seminars and journal clubs will provide the candidate with new and formal training in physiology as well as additional training in renal physiology and the responsible conduct of research. Dr. Charles Wingo, a highly regarded nephrologist and expert in renal ion transport, will serve as the candidate's mentor. An Advisory Committee has been assembled to aid the candidate in scientific and career development. Drs. Charles Wingo, Mark Segal, Julie Johnson, Barbara Battelle and Douglas Eaton are experts in the fields of nephrology, physiology, pharmacology, and neuroscience. The outstanding environment of the University of Florida, rich in clinical and basic sciences, together with the scientific plan and comprehensive training program, will offer the candidate the best opportunity for achieving her goal of becoming an independent investigator in the field of renal physiology.

Public Health Relevance

Many important physiological processes such as blood pressure and kidney function display a circadian rhythm. The link between these processes and the circadian clock is not understood. By characterizing the role of the circadian clock protein Per1 in the regulation of renal sodium transport, we can begin to understand the connection between the circadian clock, kidney function and blood pressure.

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 #
5K01DK085193-03
Application #
8245816
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2010-04-05
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$125,616
Indirect Cost
$9,305
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Gumz, Michelle L (2014) Molecular origin of the kidney clock. Kidney Int 86:873-4
Richards, Jacob; Ko, Benjamin; All, Sean et al. (2014) A role for the circadian clock protein Per1 in the regulation of the NaCl co-transporter (NCC) and the with-no-lysine kinase (WNK) cascade in mouse distal convoluted tubule cells. J Biol Chem 289:11791-806
Richards, Jacob; Diaz, Alexander N; Gumz, Michelle L (2014) Clock genes in hypertension: novel insights from rodent models. Blood Press Monit 19:249-54
Richards, Jacob; All, Sean; Skopis, George et al. (2013) Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney. Am J Physiol Regul Integr Comp Physiol 305:R735-47
Gumz, Michelle L; Rabinowitz, Lawrence (2013) Role of circadian rhythms in potassium homeostasis. Semin Nephrol 33:229-36
Stow, Lisa R; Richards, Jacob; Cheng, Kit-Yan et al. (2012) The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. Hypertension 59:1151-6
Stow, Lisa R; Gumz, Michelle L (2011) The circadian clock in the kidney. J Am Soc Nephrol 22:598-604