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。这些研究验证了以下假设：不良的社会环境通过骨髓造血细胞中β-肾上腺素能受体的威胁诱导激活来刺激未成熟促炎单核细胞（人类中为CD 16-，小鼠中为Ly-6c-高）的造血产生。具体目标将：（目的2）定义介导促炎单核细胞的威胁诱导的扩增的特异性β-肾上腺素能受体和靶细胞类型;目的3：明确介导促炎单核细胞β-肾上腺素能扩增的骨髓生成分子（包括GM-CSF、TGF-β和CXCL 12/CXCR 4趋化因子信号传导轴）。当完成时，这些研究将提供一个神经/造血通路的综合机制模型，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的“防御性编程”所涉及的基本生理机制之外，这些研究还将鉴定特定的CNS机制（例如，杏仁核中央核中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，和GM-CSF、TGF-β和/或CXCR 4的拮抗剂），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，例如动脉粥样硬化、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.