The long term goal of the proposed research project is to(determine the mechanism of acute glucocorticoid-mediated hypertension, a common clinical occurrence that is poorly understood. Traditionally, the mechanism has been thought to be the result of promiscuous activation of the renal mineralocorticoid receptor (MR) by cortisol. However, evidence suggests that the glucocorticoid receptor (GR) in renal and extra-renal tissues may also play a role, especially in the acute phase of this form of hypertension. Preliminary data indicate that this acute phase is likely mediated through changes in vascular tone. This project aims to delineate the role of vascular smooth muscle GR in the acute phase of hypertension. The investigator plans to take advantage of advances in mouse genetics by using an established in vivo mouse model which allows tissue-specific GR knock-out. By using these knock-out mice and two state-of-the-art technologies, including an implantable blood pressure monitoring system and a ultrasound probe which allows measurement^ cardiac output and systemic vascular resistance in vivo, she will be able to evaluate blood pressure responses to a variety of stimuli in an intact organism. The investigator also intends to study the vascular reactivity of isolated vessels from these knock-out mice. The vascular smooth muscle GR knock-out model is a novel reagent that will permit a full characterization of the role of this tissue in acute glucocorticoid-mediated hypertension, which previously has not been possible.

Public Health Relevance

Hypertension is a common clinical disorder and a major public health concern that is poorly understood. This work will provide improved understanding of one particular form of hypertension, lead to insight into more general forms, and direct evolving treatment strategies for hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK078623-05
Application #
8287186
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2008-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$167,940
Indirect Cost
$12,440
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Goodwin, Julie E; Feng, Yan; Velazquez, Heino et al. (2014) Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS. PLoS One 9:e108126
Goodwin, Julie E; Feng, Yan; Velazquez, Heino et al. (2013) Endothelial glucocorticoid receptor is required for protection against sepsis. Proc Natl Acad Sci U S A 110:306-11
Goodwin, Julie E; Zhang, Junhui; Gonzalez, David et al. (2011) Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. J Hypertens 29:1347-56