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Grant Details

Grant Number: 5R01CA134736-05 Interpret this number
Primary Investigator: Mathews, Herbert
Organization: Loyola University Chicago
Project Title: Immune Dysregulation By Psychosocial Distress
Fiscal Year: 2014


Abstract

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in American women. It is no surprise that women respond to a diagnosis of breast cancer with substantial psychosocial distress. Evidence from psychoneuroimmunology demonstrates that psychosocial distress impairs immune function by reducing natural killer cell activity (NKCA) and the production of interferon (IFN) gamma. Both NKCA and IFN gamma contribute to protection from tumor initiation, primary tumor growth, and tumor metastasis. Of note, epithelial tumors, like those of the breast, are responsive to NK cells and IFN gamma; hence, reductions in these forms of immune defense are relevant to breast cancer. We show that women diagnosed with breast cancer experience psychosocial distress, which is accompanied by elevated levels of cortisol, decreased NKCA, and reduced IFN gamma production. The purpose of this project is to determine whether epigenetic pattern underlies the mechanism for the immune dysregulation that occurs with a diagnosis of breast cancer. Aim 1 will longitudinally assess women diagnosed with early stage breast cancer and evaluate the trajectory of their psychosocial, cortisol, and immune response with respect to their peripheral blood mononuclear (PBMC) epigenetic pattern. In Aims 2 and 3, these relationships will be investigated at the cellular and molecular level. Aim 2 will determine whether PBMC epigenetic pattern is associated with changes in the cellular levels of IFN gamma and/or perforin, two key effector molecules in cancer control. Aim 3 will determine whether PBMC epigenetic pattern is associated with changes in chromatin accessibility for the promoter regions of IFN gamma and/or perforin. Lastly, Aim 4 will evaluate an explanatory model that posits mediated relationships among the psychobiological variables. Latent growth curve analysis will be used to identify and evaluate the trajectories of the study variables with regard to PBMC epigenetic pattern. This project will provide a mechanistic understanding of immune dysregulation, consequent to psychosocial distress, and has the potential to spur development of new approaches to identify and manage individuals at risk for psychosocial distress mediated immune dysregulation.



Publications

Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction.
Authors: Misale M.S. , Witek Janusek L. , Tell D. , Mathews H.L. .
Source: Brain, behavior, and immunity, 2018 Jan; 67, p. 279-289.
EPub date: 2017-09-12.
PMID: 28911980
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Epigenetics and social context: implications for disparity in cardiovascular disease.
Authors: Saban K.L. , Mathews H.L. , DeVon H.A. , Janusek L.W. .
Source: Aging and disease, 2014 Oct; 5(5), p. 346-55.
EPub date: 2014-10-01.
PMID: 25276493
Related Citations

Glucocorticoids regulate natural killer cell function epigenetically.
Authors: Eddy J.L. , Krukowski K. , Janusek L. , Mathews H.L. .
Source: Cellular immunology, 2014 Jul; 290(1), p. 120-30.
EPub date: 2014-06-18.
PMID: 24978612
Related Citations

Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer.
Authors: Witek Janusek L. , Tell D. , Albuquerque K. , Mathews H.L. .
Source: Brain, behavior, and immunity, 2013 Mar; 30 Suppl, p. S149-62.
EPub date: 2012-06-01.
PMID: 22659062
Related Citations

Telomeres and epigenetics: potential relevance to chronic pain.
Authors: Sibille K.T. , Witek-Janusek L. , Mathews H.L. , Fillingim R.B. .
Source: Pain, 2012 Sep; 153(9), p. 1789-1793.
EPub date: 2012-07-05.
PMID: 22770844
Related Citations

Glucocorticoid receptor mediated suppression of natural killer cell activity: identification of associated deacetylase and corepressor molecules.
Authors: Bush K.A. , Krukowski K. , Eddy J.L. , Janusek L.W. , Mathews H.L. .
Source: Cellular immunology, 2012 Jan-Feb; 275(1-2), p. 80-9.
EPub date: 2012-03-21.
PMID: 22483981
Related Citations

Epigenetic patterns associated with the immune dysregulation that accompanies psychosocial distress.
Authors: Mathews H.L. , Konley T. , Kosik K.L. , Krukowski K. , Eddy J. , Albuquerque K. , Janusek L.W. .
Source: Brain, behavior, and immunity, 2011 Jul; 25(5), p. 830-9.
EPub date: 2010-12-10.
PMID: 21146603
Related Citations

Glucocorticoid dysregulation of natural killer cell function through epigenetic modification.
Authors: Krukowski K. , Eddy J. , Kosik K.L. , Konley T. , Janusek L.W. , Mathews H.L. .
Source: Brain, behavior, and immunity, 2011 Feb; 25(2), p. 239-49.
EPub date: 2010-07-23.
PMID: 20656012
Related Citations

Epigenetics and psychoneuroimmunology: mechanisms and models.
Authors: Mathews H.L. , Janusek L.W. .
Source: Brain, behavior, and immunity, 2011 Jan; 25(1), p. 25-39.
EPub date: 2010-09-09.
PMID: 20832468
Related Citations

Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy.
Authors: Witek-Janusek L. , Gabram S. , Mathews H.L. .
Source: Psychoneuroendocrinology, 2007 Jan; 32(1), p. 22-35.
EPub date: 2006-11-07.
PMID: 17092654
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