Social regulation of pro-inflammatory monocytes

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。这些研究验证了一个假设，即不利的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，刺激未成熟的促炎单核细胞（人的CD16-，小鼠的ly -6c-高）的造血生成。具体目标将：（目标1）确定慢性威胁上调促炎单核细胞的神经和内分泌途径；（目的2）明确特异性β -肾上腺素能受体和介导炎性单核细胞威胁诱导扩增的靶细胞类型；（Aim 3）定义介导促炎单核细胞β -肾上腺素能扩张的骨髓生成分子（包括GM-CSF、tgf - β和CXCL12/CXCR4趋化因子信号轴）。一旦完成，这些研究将提供一个神经/造血途径的综合机制模型，慢性逆境可以通过该途径上调循环免疫细胞中的炎症基因表达。这些研究的首要目标是建立一个全面的理论，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”的基本生理机制外，这些研究还将确定特定的中枢神经系统机制（例如，杏仁核中央的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，GM-CSF， tgf - β和/或CXCR4的拮抗剂），以及机制生物标志物(例如，这些研究可以应用于未来的研究，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。

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.