Social regulation of pro-inflammatory monocytes

促炎单核细胞的社会调节

基本信息

批准号：
9271142
负责人：
STEVE W COLE
金额：
$ 31.56万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9271142
关键词：
Adrenergic Agents Adrenergic Antagonists Alzheimer&apos s Disease American Amygdaloid structure Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Behavioral Model Bereavement Biological Biological Markers Blood Vessels Bone Marrow CXCL12 gene CXCR4 gene Cell Nucleus Cells Chronic Chronic stress Complement Factor B Development Diagnosis Disease Endocrine Experimental Animal Model FCGR3B gene Foundations Future Gene Activation Gene Expression Genes Genetic Genetic Models Genetic Transcription Glucocorticoids Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Health Health Status Heart Diseases Hematopoietic Hematopoietic stem cells Human Hypothalamic structure Immune Immune system Individual Inflammation Inflammatory Intervention Life Link Literature Malignant Neoplasms Mediating Mesenchymal Stem Cells Metabolic Modeling Molecular Molecular Target Morbidity - disease rate Mus Myelogenous Myeloid Cells Myelopoiesis Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Osteoblasts Pathway interactions Pharmacology Phenotype Physiological Pituitary-Adrenal System Play Population Poverty Production Public Health Regulation Research Risk Risk Factors Role Signal Transduction Social Conditions Social Environment Social isolation Stress Stromal Cells System Testing Transforming Growth Factor beta Transforming Growth Factors Up-Regulation beta-adrenergic receptor cardiovascular risk factor cell type chemokine epidemiology study genetic manipulation granulocyte health disparity improved infectious disease model low socioeconomic status macrophage molecular marker monocyte mortality mouse model neoplastic neural model neuromechanism overexpression progenitor public health relevance receptor relating to nervous system response social social genomics theories transcriptome

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：拟议的研究旨在通过上调促炎基因的表达来确定不良社会环境如何影响与炎症相关疾病的风险。这些研究检验了以下假设，即不良社会环境通过威胁诱导的β-肾上腺素能受体的激活在骨髓骨髓骨髓细胞中刺激了未成熟的促炎单核细胞的造血产生（人类中的CD16-，小鼠中的LY-6C高）。具体目的将：（目标1）定义慢性威胁上调促炎单核细胞的神经和内分泌途径；（AIM 2）定义特定的β-肾上腺素受体和靶细胞类型，介导威胁引起的炎性单核细胞的扩张；（AIM 3）定义介导促炎单核细胞（包括GM-CSF，TGF-BETA和CXCL12/CXCR4趋化因子信号轴）的介导β-肾上腺素能扩张的骨髓分子。完成后，这些研究将提供神经 /造血途径的综合机械模型，慢性逆境可以上调循环免疫细胞中的炎症基因表达。这些研究的总体目标是开发一种综合理论，该理论解释了共同的社会风险因素如何影响多种与炎症有关的疾病。除了阐明免疫系统转录组“防御性编程”涉及的基本生理机制外，这些研究还将确定特定的CNS机制（例如，杏仁核中心核中CRF基因激活），药理学干预策略（例如，Beta-2和Beta-3和Beta-3和Beta-3 eNTRENERG-BET-BET-BETANERGIF-BETAGANIST ANTGANIST和GMFONISTS，THENG ANTGANISS，THEMALICIC PARINGITIC策略和/或CXCR4），以及机械生物标志物（例如，骨髓骨髓分子和循环单核细胞表型），可以应用于未来的研究中，以阐明压力诱导的促炎单核细胞的上调如何影响特定的炎症疾病，例如特定的疾病疾病，例如类疾病，例如，疾病疾病疾病疾病，静脉内疾病的疾病和疾病的疾病。