The proposed research seeks to determine how adverse social environments influence the risk of inflammation-related disease by up-regulating the expression of pro-inflammatory genes. These studies test the hypothesis that adverse social environments stimulate the hematopoietic production of immature pro-inflammatory monocytes (CD16- in humans, Ly-6c-high in mice) via threat-induced activation of beta-adrenergic receptors in bone marrow myelopoietic cells.
Specific aims will:
(Aim 1) Define the neural and endocrine pathways by which chronic threat up-regulates pro-inflammatory monocytes;
(Aim 2) Define the specific beta-adrenergic receptors and target cell types mediating threat-induced expansion of pro- inflammatory monocytes;
and (Aim 3) Define the myelopoietic molecules mediating beta-adrenergic expansion of pro-inflammatory monocytes (including GM-CSF, TGF-beta, and the CXCL12/CXCR4 chemokine signaling axis). When complete, these studies will provide an integrated mechanistic model of the neural / hematopoietic pathway by which chronic adversity can up-regulate inflammatory gene expression in circulating immune cells. The overarching goal of these studies is to develop a comprehensive theory that explains how common social risk factors can influence multiple inflammation-related diseases. In addition to clarifying the basic physiologic mechanisms involved in """"""""defensive programming"""""""" of the immune system transcriptome, these studies will identify specific CNS mechanisms (e.g., Crf gene activation in central nucleus of the amygdala), pharmacologic intervention strategies (e.g., beta-2 and beta-3 adrenergic antagonists, and antagonists of GM-CSF, TGF-beta, and/or CXCR4), and mechanistic biomarkers (e.g., myelopoietic molecules and circulating monocyte phenotypes) that can be applied in future studies to clarify how stress-induced up- regulation of pro-inflammatory monocytes impacts specific inflammation-related diseases such as atherosclerosis, Type II diabetes, Alzheimer's disease, and cancer.
This research seeks to improve public health by clarifying the biological pathways through which adverse social environments such as social isolation or poverty influence the risk of inflammation-related diseases such as heart disease, Alzheimer's disease, and cancer. This research will establish new risk factors, neural mechanisms, pharmacologic intervention strategies, and cellular and molecular biomarkers of individual health status to help protect human health in the context of adverse social environments and thus reduce socially-related health disparities.
| Murray, Damian R; Haselton, Martie G; Fales, Melissa et al. (2018) Falling in love is associated with immune system gene regulation. Psychoneuroendocrinology 100:120-126 |
| Armer, Jessica S; Clevenger, Lauren; Davis, Lauren Z et al. (2018) Life stress as a risk factor for sustained anxiety and cortisol dysregulation during the first year of survivorship in ovarian cancer. Cancer 124:3401-3408 |
| Lutgendorf, Susan K; Thaker, Premal H; Arevalo, Jesusa M et al. (2018) Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma. Cancer 124:580-586 |
| Mehl, Matthias R; Raison, Charles L; Pace, Thaddeus W W et al. (2017) Natural language indicators of differential gene regulation in the human immune system. Proc Natl Acad Sci U S A 114:12554-12559 |
| Shaashua, Lee; Shabat-Simon, Maytal; Haldar, Rita et al. (2017) Perioperative COX-2 and ?-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res 23:4651-4661 |
| Chun, K; Capitanio, J P; Lamkin, D M et al. (2017) Social regulation of the lymph node transcriptome in rhesus macaques (Macaca mulatta). Psychoneuroendocrinology 76:107-113 |
| Lamkin, Donald M; Ho, Hsin-Yun; Ong, Tiffany H et al. (2016) ?-Adrenergic-stimulated macrophages: Comprehensive localization in the M1-M2 spectrum. Brain Behav Immun 57:338-346 |
| Moieni, Mona; Irwin, Michael R; Jevtic, Ivana et al. (2015) Trait sensitivity to social disconnection enhances pro-inflammatory responses to a randomized controlled trial of endotoxin. Psychoneuroendocrinology 62:336-42 |
| Cole, Steven W; Levine, Morgan E; Arevalo, Jesusa M G et al. (2015) Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. Psychoneuroendocrinology 62:11-7 |
| Cole, Steven W (2014) Human social genomics. PLoS Genet 10:e1004601 |
