Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

抗原呈递细胞对脂肪组织炎症的调节

基本信息

批准号：
9234511
负责人：
Carey N Lumeng
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-11 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234511
关键词：
Address Adipocytes Adipose tissue Adult Antigen Presentation Antigen Presentation Pathway Antigen Targeting Antigen-Presenting Cells Antigens Autoimmune Diseases Biological Assay Biology Birth Body Weight decreased CD4 Positive T Lymphocytes Caloric Restriction Cardiovascular Diseases Cell Communication Cell physiology Cells Child health care Clinical Clinical Research Communication Complex Cross-Sectional Studies Data Dendritic Cells Development Diabetes Mellitus Diet Disease Equilibrium Fatty acid glycerol esters Female Fostering Functional disorder Funding Goals Grant Homeostasis Human Human Biology Immune Immune Tolerance Immune response Immune system Immunity Immunologics In Vitro Individual Inflammation Inflammatory Insulin Resistance Interleukin-6 Lead Leukocytes Link Maintenance Malignant Neoplasms Memory Metabolic Metabolic Diseases Metabolic syndrome Metabolism Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Pathogenesis Pathologic Pathway interactions Patients Phenotype Population Property Receptor Signaling Regulation Regulatory T-Lymphocyte Research Role Shapes Signal Transduction Stimulus T-Cell Activation T-Cell Receptor T-Lymphocyte Thinness Visceral Work adaptive immune response bariatric surgery base clinically relevant in vivo innovation insight macrophage male mouse model new therapeutic target novel nutrient metabolism polarized cell pre-clinical preclinical study public health relevance response sex subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Obesity threatens the health of children and adults in the U.S. based on its strong association with metabolic syndrome and Type 2 diabetes. The pro-inflammatory state induced by obesity has been directly linked to metabolic disease and is driven by inflammatory changes in adipose tissue. This is driven by adipose tissue leukocytes such as macrophages (ATM) and T cells that provide signals that can both positively and negatively influence nutrient metabolism by regulating adipocyte function. The mechanisms that govern the choice to either promote metabolic homeostasis or dysregulation are not well delineated. Revealing the mechanisms that govern the immune balance in adipose tissue will provide insight into new pathways that can be modified for new treatments for diabetes and other cardiometabolic disease. Antigen presenting cells (APCs) sit at the interface between innate and adaptive immune responses and associations between antigen presentation pathways and metabolic disease are well documented. We have discovered that direct communication between macrophages and CD4+ T cells in adipose tissue is a critical control point in the decision to generate regulatory/protective or immunostimulatory/pro-inflammatory signals. The identity of the signals that shape the adipose tissue immune response, when is regulation favored over immunity, which antigen presenting cells should be targeted for new therapeutics, and how these functions differ between metabolically healthy and unhealthy obese patients are unknown. This proposal will address these questions in pursuit of our long term goal of identifying the features of the adipose tissue immune system that contribute metabolic disease. This study will examine the hypothesis that ATM and adipose tissue dendritic cells (ATDC) control the phenotype of CD4+ T lymphocytes via APC function. This hypothesis is supported by our work in the prior funding cycle, but is enhanced by our recent unambiguous identification of ATDC, demonstration that ATM and ATDC differentially control metabolism and regulatory T cells, and identification of associations between MHCIIhi populations of ATMs in obese patients with diabetes. These findings drive the specific aims of the proposal which are: (1) To delineate the roles of ATMs and ATDCs in obesity-induced adipose tissue inflammation and T cell activation. (2) To assess the effects of weight loss on adipose tissue antigen presentation cell function. (3) To evaluate the association between ATM and ATDCs and diabetes status in obese humans. Completing our aims will have a significant impact on identifying the important communication pathways that shape the range of responses that can be generated by adipose tissue leukocytes. This is a required step in understanding how the adipose tissue immune system may be manipulated to either promote immune "tolerance" to obesity or block immunostimulatory signals. It will use innovative complementary studies to close the gap between our understanding of adipose tissue leukocyte biology in pre-clinical and clinical studies.

描述（由适用提供）：肥胖会威胁到美国与代谢综合征和2型糖尿病的牢固联系，威胁到美国的儿童和成人的健康。肥胖引起的促炎状态与代谢疾病直接相关，并由脂肪组织的炎症变化驱动。这是由脂肪组织白细胞（例如巨噬细胞（ATM）和T细胞）驱动的，这些信号可以通过控制脂肪细胞功能来积极和负面影响营养代谢。促进代谢稳态或失调的选择的机制并未得到很好的描述。揭示了控制脂肪组织免疫平衡的机制，将为您提供有关新途径的见解，这些途径可以修改为糖尿病和其他心脏代谢疾病的新疗法。抗原呈递细胞（APC）位于先天性和适应性免疫回报之间的界面以及抗原表现途径与代谢疾病之间的关联。我们发现，巨噬细胞和脂肪组织中CD4+ T细胞之间的直接通信是决定生成调节/保护性或免疫刺激/促炎性信号的关键控制点。塑造脂肪组织免疫响应的信号的身份，何时受到免疫学的调节，抗原呈递细胞应针对新的治疗剂，以及这些功能在代谢健康和不健康的肥胖患者之间如何有所不同。该提案将解决这些问题，以追求我们确定促成代谢疾病的脂肪组织免疫系统的特征的长期目标。这项研究将研究以下假设：ATM和脂肪组织树突状细胞（ATDC）通过APC功能控制CD4+ T淋巴细胞的表型。我们在先前的资金周期中的工作支持了这一假设，但是通过我们最近对ATDC的明确鉴定，ATM和ATDC对ATM和ATDC进行了不同控制的代谢和调节性T细胞的证明以及对糖尿病患者肥胖患者ATMS的MHCIIHI人群的关联的增强。这些发现推动了提案的具体目的，该目的是：（1）描述ATM和ATDC在肥胖诱导的脂肪组织注射和T细胞激活中的作用。（2）评估体重减轻对脂肪组织抗原表现细胞功能的影响。（3）评估肥胖人类中ATM和ATDC与糖尿病状况之间的关联。完成我们的目标将对确定塑造脂肪组织白细胞可以产生的响应范围的重要沟通途径产生重大影响。这是了解如何操纵脂肪组织免疫系统以促进肥胖“耐受性”或阻止免疫刺激信号的免疫的必要步骤。它将使用创新的互补研究来弥合我们在临床前和临床研究中对脂肪组织白细胞生物学的理解之间的差距。