Social regulation of pro-inflammatory monocytes

促炎单核细胞的社会调节

• 批准号: 8629640
• 负责人: STEVE W COLE
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8629640
• 关键词: Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Alzheimer' 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; Development; Diagnosis; Disease; Endocrine; Epidemiologic Studies; Experimental Animal Model; FCGR3B gene; Foundations; Future; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic Models; Glucocorticoids; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Health; Health Status; Heart Diseases; Hematopoietic; Hematopoietic stem cells; Hereditary Disease; 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; 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; Stem cells; Stress; Stromal Cells; System; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Up-Regulation; adrenergic; beta-adrenergic receptor; cardiovascular risk factor; cell type; chemokine; gene therapy; genetic manipulation; granulocyte; health disparity; improved; infectious disease model; low socioeconomic status; macrophage; monocyte; mortality; mouse model; neoplastic; neural model; neuromechanism; progenitor; programs; receptor; relating to nervous system; response; social; social genomics; stem; theories

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）：拟议的研究旨在确定不利的社会环境如何通过上调促炎基因的表达来影响炎症相关疾病的风险。这些研究检验了以下假设：不良社会环境通过威胁诱导骨髓生成细胞中 β-肾上腺素能受体的激活，刺激未成熟促炎单核细胞（人类 CD16-，小鼠 Ly-6c-high）的造血生成。具体目标将：（目标 1）定义慢性威胁上调促炎性单核细胞的神经和内分泌途径； （目标 2）定义介导威胁诱导的促炎性单核细胞扩张的特定 β-肾上腺素能受体和靶细胞类型； （目标 3）定义介导促炎性单核细胞 β 肾上腺素能扩张的骨髓生成分子（包括 GM-CSF、TGF-β 和 CXCL12/CXCR4 趋化因子信号传导轴）。完成后，这些研究将提供神经/造血途径的综合机制模型，通过该模型，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发展一种综合理论，解释常见的社会风险因素如何影响多种炎症相关疾病。除了阐明免疫系统转录组“防御性编程”所涉及的基本生理机制外，这些研究还将确定特定的 CNS 机制（例如杏仁核中央核中的 Crf 基因激活）、药理学干预策略（例如 β-2 和 β-3 肾上腺素能拮抗剂，以及 GM-CSF、TGF-β 的拮抗剂）。 和/或 CXCR4）和机制生物标志物（例如骨髓生成分子和循环单核细胞表型）可用于未来的研究，以阐明应激诱导的促炎单核细胞上调如何影响特定的炎症相关疾病，如动脉粥样硬化、II 型糖尿病、阿尔茨海默病和癌症。