Role of Glucocorticoid Signaling in Metabolic Syndrome and Diabetes
The long-term goals of our research are to identify potential therapies that could be used to treat diabetes and the metabolic syndrome. Specifically we are exploring the following questions:
Glucocorticoids are stress hormones released by the adrenal gland. Glucocorticoids are known to have anti-inflammatory properties and are commonly used for the treatment of common inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis and Crohn’s disease), and chronic obstructive pulmonary disease (COPD/emphysema). However, glucocorticoid treatment is accompanied by a slew of adverse metabolic effects including osteoporosis (weakening of the bones that can result in fractures), obesity, diabetes, high blood pressure, high blood cholesterol levels, myopathy (muscle wasting), thin skin and cognitive effects. Glucocorticoids are known to cause diabetes and to exacerbate diabetes in diabetics and have been implicated in the etiology of metabolic syndrome. Our laboratory is focused on the molecular mechanisms of glucocorticoid action. We are focused on the Glucocorticoid Receptor (GR) a member of the nuclear hormone receptor family.
A. What tissues are responsible for the various effects of glucocorticoids? This is not as straight forward as it might seem. For example glucocorticoid mediated muscle wasting could be a direct effect on muscle or could be an effect on liver which makes IGF-1 to stimulate muscle growth. To answer this question we are making tissue specific GR KO mice using the cre-lox system.
B. What gene regulatory events (and in what tissues) are responsible for glucocorticoid-mediated effects? Identification of physiologically relevant target genes could result in novel therapies for the treatment of diabetes and metabolic syndrome. We use genomic approaches such as Chromatin immunoprecipitation followed by deep sequencing to answer these questions.
C. Which effector arms of glucocorticoid signaling are responsible for the various physiological effects? In order to answer this question we examine GRdim mice with a point mutation rendering GR unable to form dimers.
D. What is the physiological significance of GR post-translational modifications? We have genetically engineered mice using CRISPRs to make point mutations coding for serine to alanine mutations in serine residues known to be phosphorylated.
We are interested in non-classical functions of adipose tissue. Previously, the dogma was that adipose tissue merely served as a fuel reserve to store triglyceride fat. However, more recently additional functions have been discovered. The adipose tissue is an endocrine organ that secretes hormones (e.g. leptin, adiponectin) with robust physiological effects. To understand potential roles of adipose tissue, we have genetically engineered mice that completely lack adipose tissue. These mice have robust phenotypes with respect to glucose and lipid metabolism, reproduction, bone biology, and thermoregulation. We continue to study these mice to gain insights into novel functions of adipose tissue.
Charles Harris, MD/PhD
821 SouthWest Tower
815 SouthWest Tower
Washington University School of Medicine
660 South Euclid Avenue
St. Louis, MO 63110
4940 Parkview Place
St. Louis, MO 63110.
We are constantly on the look out for talented undergraduates, graduate students, medical students, fellows, post-docs and visiting scientists!
Charles Harris, MD/PhD
Irina Hutson, MS
Senior Research Technician
Kevin Bauerle, MD/PhD
Washington University Endocrine Fellow
Sandip Kumar Bose, PhD
Postdoctoral Research Fellow
Undergraduate Student at Washington University (summer student)
Undergraduate at Rhodes College
Undergraduate SUNY Stony Brook.
I went to Brown University for undergraduate and then Washington University School of Medicine for MD/PhD and residency in internal medicine before going to UCSF for an endocrinology fellowship. I returned to Washington University as faculty member in the Division of Endocrinology Metabolism & Lipid Research in 2013. I became fascinated with glucocorticoids during my clinical endocrinology fellowship at UCSF when I saw many patients with Cushing’s disease under the mentorship of Blake Tyrrell, MD. I forged my path studying molecular mechanisms of glucocorticoid action in the lab of Robert Farese, Jr. at the Gladstone Institutes.
I obtained my MS from Purdue and then worked for several years at the UM-Columbia Diabetes Research Center before joining the Harris lab in 2013. I assist in all lab projects described below as well as performing lab manager duties.
I obtained my MD/PhD (Cancer Biology) from the University of Colorado. I moved to Boston for internal medicine residency at Beth Israel Deaconess Medical Center and ultimately short-tracked into my endocrinology fellowship at Washington University in 2014. I am currently a 3rd year fellow. In a broad sense, I am interested in the role of nuclear hormone receptors in an array of disease processes, ranging from type 2 diabetes and metabolic syndrome to chronic inflammatory conditions and cancer. This led me to join the lab of Dr. Harris where my research currently focuses on the role of the glucocorticoid receptor in adipocyte development and function.
My work in the laboratory is to understand the role of GR in metabolic disorder. Since GR knockout (GRKO) mice exhibit peri-natal lethality due to respiratory failure, we have developed tissue specific GRKO mice (adipose and liver) by using cre-lox technology to study the role of GR in metabolic disorder.
Reuben has spent two summers in the Harris lab performing research on mice with CRISPR modified glucocorticoid receptor (GR). His first summer was spent corroborating the new model of CRISPR alteration to the GR gene. He performed Western blots and luciferase transactivation and transrepression assays to understand both the presence and functionality of GR in the mice. His second summer was spent characterizing an extra mutation in the GR that prevents the birth of mice homozygous for the specific mutation. To do this, he again utilized Western blots and luciferase assays.
Hi, I’m Augie. I am a summer intern in the lab, and am currently working on a bioassay using a reporter cell line to detect low concentrations of estradiol in mouse samples, since most industry ELISA kits are unable to detect the level of estrogen regularly found in mice urine. This summer I’ve also been testing the effect of dexamethasone on adipocyte lipolysis in order to study the in vitro effects of glucocorticoids on adipocyte triglyceride metabolism.
Ioana is visiting the lab as part of the 2016 Amgen Scholars program and is working on better understanding the anti-inflammatory properties of glucocorticoids, particularly from a transrepression perspective. This has included identifying pro-inflammatory genes that are strongly induced by bacterial lipopolysaccharide in mouse embryonic fibroblasts and repressed significantly by the synthetic glucocorticoid dexamethasone. From the perspective of these genes and with the use of reverse transcriptase qPCR, she is also investigating how various glucocorticoid receptor mutations affect the repression capabilities of the dexamethasone. Finally, she is trying to determine if a pre-clinical drug marketed for Cushing’s Disease has any glucocorticoid transrepression effects on pro-inflammatory genes.
Harris Lab at Cardinals Game
Medical Student at Creighton University
DBBS Rotation Student.
Medical Student Florida International University.
Medical Student SUNY Stony Brook
2011 – 2013
Smita Mascharak, Research Technician
Medical Student UCLA
Med-Peds Resident, UPMC
UTSW Medicine Resident
UCSF BMS Graduate Student
- Bose S, Hutson I, Harris C. Hepatic glucocorticoid receptor plays a greater role than adipose GR in metabolic syndrome despite renal compensation. In preparation
- Mascharak S, Varonin JP, Farese RV Jr., Harris C Glucocorticoid induced obesity is DGAT1 dependent. In preparation.
- Harris, C. (2015) Animal Models of Altered Glucocorticoid Signaling. Adv Exp Med Biol 872, 337-352.
- Harris, C. (2015) Clinical Perspective: What Do Addison and Cushing Tell Us About Glucocorticoid Action? Adv Exp Med Biol 872, 83-96.
- Roohk DJ, Mascharak S, Khambatta C, Leung H Hellerstein, M, Harris C. Dexamethasone Mediated Changes in Adipose Triacylglycerol Metabolism Are Exacerbated in the Absence of a Functional GR Dimerization Domain. Endocrinology. 2013;154(4):1528-39. PMID:23493372. PMCID:PMC3602623.
- Kuo T, Harris C, Wang JC. Metabolic Functions of Glucocorticoid Receptor in Skeletal Muscle. Molecular and Cellular Endocrinology. 2013. Mol Cell Endocrinology S0303-7207(13)00088-9. PMID:23523565
- Harris, C, Roohk DJ, Boudignon B, Halloran B, Hellerstein M Large increases in adipose triacylglycerol flux in Cushingoid CRH-Tg mice are explained by futile cycling. Am J Physiol Endocrinol Metab. 2013 304(3):E282-93. PMID: 23211515. PMCID: PMC3566431
- Wang JC, Gray NE, Kuo T, Harris C. Regulation of triglyceride metabolism by glucocorticoid receptor. Cell Biosci 2012: 2: 19.PMID:22640645. PMCID: PMC3419133
- Kuo T, Lew MJ, Mayba O, Harris C, Speed TP, Wang JC. Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling. PNAS 2012: 109 (28): 11160-11165. PMID: 22733784. PMCID: PMC3396543
- Yu CY, Mayba O, Lee JV, Tran J, Harris C, Speed T, Wang JC. Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS ONE 2010: 5(12): e15188. PMID: 21187916. PMCID: PMC3004788
- Schweiger M, Camus G, Herker E, Harris C, Tsou C, Farese RV Jr, , Herath K, Previs S, Roddy T, Pinto S, Zechner R, Ott M. The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem. 2014 Dec 26;289(52):35770-80.PMID:25381252. PMCID:PMC4276846
- Harris C, Herker E, Farese RV Jr, Ott M. Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis. J Biol Chem 2011: 286(49): 42615-25. PMID: 21984335. PMCID: PMC3234948
- Herker, E., Harris, C., Hernandez, C., Carpentier, A., Kaehlcke, K., Rosenberg, A. R., Farese, R. V., Jr., and Ott, M. (2010) Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 16, 1295-1298
- Harris C. Mutant prolactin receptor and familial hyperprolactinemia. N Engl J Med. 2014 Mar 6;370(10):976. doi: 10.1056/NEJMc1315848#SA1.
- Marcus JF, Harris C, Goodin DS, Josephson SA. Acute hypercalcemia following excessive calcium supplementation in a dehydrated patient with progressive multiple sclerosis: vitamin D supplementation is a red herring – Reply. Arch Neurol. 2012; 69(6): 793-794 PMID: 22232355
- Marcus JF, Shalev SM, Harris C, Goodin DS, Josephson SA. Severe hypercalcemia following vitamin d supplementation in a patient with multiple sclerosis: a note of caution. Arch Neurol 2012: 69: 129-132. PMID: 21364286
- Sos B, Harris C, Nordstrom SM, Tran JL, Balazs M, Calpazi P, Febbriao M, Applegate MAB, Wagner KU, Weiss EJ. Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. J Clin Invest 2011: 121(4): 1412–1423. PMID: 21364286. PMCID: PMC3069761
- Harris C, Haas J , Streeper R, Stone S, Kumari M, Yang K, Han X, Brownell N, Gross R, , Zechner, R, Farese RV, Jr. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J Lipid Res 2011: 52:(4): 657-667. PMID: 21317108. PMCID: PMC3284159
Articles available via MyBibliography at NCBI: http://www.ncbi.nlm.nih.gov/sites/myncbi/10aD-zATgscA-/bibliography/46198389/public/?sort=date&direction=ascending
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