Therapeutic Opportunities of Targeting Tissue Factor Signaling in Obesity

肥胖症中靶向组织因子信号传导的治疗机会

基本信息

批准号：
8440322
负责人：
FAHUMIYA SAMAD
金额：
$ 57.57万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
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：
2011-06-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440322
关键词：
Adipocytes Adipose tissue Antibodies Attenuated Binding Blocking Antibodies Bone Marrow Bone Marrow Transplantation Cardiovascular Diseases Cells Chimera organism Coagulation Process Coupled Cytoplasmic Tail Data Dendritic Cells Development Diet Disease Eating Energy Metabolism Epidemic Factor VIIa Fatty acid glycerol esters Feeding behaviors GTP-Binding Proteins Gene Expression Gene Targeting Goals Grant Health Hematopoietic Hemorrhage Human Hyperphagia ITGAX gene In Vitro Inflammation Inflammatory Insulin Resistance Knock-in Mouse Knockout Mice Leptin Leptin resistance Measures Mediating Messenger RNA Metabolic Metabolic syndrome Metabolism Molecular Monoclonal Antibodies Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity PAR-2 Receptor Pathogenesis Pathology Pathway Analysis Pathway interactions Phenotype Play Proteinase-Activated Receptors Proteins Research Role Signal Pathway Signal Transduction Simulate Societies Testing Therapeutic Thromboplastin Transgenic Mice Transplantation Chimera Weight Weight Gain Wild Type Mouse angiogenesis blood glucose regulation cell type cellular targeting combat diabetic fatty acid oxidation feeding human tissue improved inhibiting antibody innovation insight lipid biosynthesis macrophage minimal risk mouse model novel novel strategies obesity treatment receptor research study response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in western societies. However, mechanisms contributing to its pathology are incompletely understood, and, treatment options remain limited. Our goal is to evaluate a novel approach, antibodies that inhibit tissue factor (TF) signaling, in the treatment of obesity and the metabolic syndrome. In addition to its procoagulant role, TF has coagulation-independent functions in inflammation and angiogenesis. Thus, binding of VIIa to TF also leads to direct signaling via the G-protein coupled protease activated receptor-2 (PAR2). The high fat diet (HFD) fed C57BL/6J mouse model of obesity simulates the human condition, including feeding behavior (hyperphagia), weight gain/energy metabolism, and the development of the metabolic syndrome characterized by insulin resistance and type 2 diabetes. We show that TF and PAR2 are co expressed in adipose tissues (AT) and elevated in adipose tissues of HFD-induced obese mice. Moreover, mice lacking the cytoplasmic domain of TF (TF4CT mice) or PAR2 are protected from HFD- induced obesity and the subsequent development of insulin resistance. In obese wild-type mice, an antibody that blocks TF-VIIa binding rapidly improves insulin resistance. Insulin resistance was also ameliorated in obese transgenic mice that express human TF when they were treated with a monoclonal antibody that specifically blocked TF signaling. The overall goal of this grant is to characterize the contributions of TF signaling to the pathogenesis of obesity with the long term goal to advance a rational pharmacological targeting of this pathway to combat obesity and its complications. In Aim 1 we will use Wild type, TF4CT , PAR2-/-, and double deficient TF4CT /PAR2-/- mice together with bone marrow (BM) chimeras and adipocytes isolated from these knock-out mice to characterize the contribution, cellular targets and mechanisms by which TF-VIIa- PAR2 signaling supports the development of obesity. In Aim 2 we will use a variety of approaches including BM chimeras of TF4CT and PAR2-/- mice and isolated AT macrophages to validate that macrophage TF-PAR2 signaling contributes to adipose inflammation and insulin resistance. In Aim 3 we will characterize the mechanism and efficacy of anti-TF treatment strategies in reversing obesity and insulin resistance. Evaluating the effect of monoclonal antibodies that selectively inhibit direct TF-VIIa-PAR2 signaling in transgenic mice expressing human TF will determine the therapeutic potential of such a strategy that carries minimal risk of bleeding complications. These studies will provide fundamental insights into the role of TF signaling in obesity, and test an innovative therapeutic approach in these pathways to improve metabolic complications of obesity.

描述（由申请人提供）：肥胖已经达到了西方社会的流行比例。但是，促成其病理学的机制尚不完全了解，并且治疗方案仍然有限。我们的目标是评估一种新的方法，即抑制组织因子（TF）信号传导的抗体，以治疗肥胖和代谢综合征。除了其凝聚作用外，TF在炎症和血管生成中具有与凝血无关的功能。因此，VIIA与TF的结合还导致通过G蛋白偶联蛋白酶激活受体-2（PAR2）的直接信号传导。饲喂C57BL/6J小鼠肥胖小鼠模型的高脂肪饮食（HFD）模拟了人类状况，包括喂养行为（肥大），体重增加/能量代谢以及以胰岛素抵抗和2型糖尿病为特征的代谢综合征的发展。我们表明，TF和PAR2在脂肪组织（AT）中表达，并在HFD诱导的肥胖小鼠的脂肪组织中升高。此外，缺乏TF（TF4CT小鼠）或PAR2的细胞质结构域的小鼠受到HFD诱导的肥胖症的保护，并随后胰岛素抵抗的发展。在肥胖的野生型小鼠中，阻断TF-VIIA结合的抗体迅速改善了胰岛素抵抗。当用单克隆抗体处理特异性阻断TF信号传导的单克隆抗体时，还可以在肥胖的转基因小鼠中改善胰岛素耐药性。该赠款的总体目标是表征TF信号对肥胖症发病机理的贡献，其长期目标是促进这种途径对抗肥胖及其并发症的理性药理靶向。在AIM 1中，我们将使用野生型，TF4CT，PAR2 - / - 和双重缺陷的TF4CT/PAR2 - / - 小鼠以及骨髓（BM）嵌合体（BM）嵌合体和脂肪细胞与这些敲除小鼠中分离出来，以表征TF-VIIA- PAR2信号信号的贡献，细胞靶和机制，以表征TF-VIIA- PAR2信号的发展。在AIM 2中，我们将使用各种方法，包括TF4CT和PAR2 - / - 小鼠的BM嵌合体，并在巨噬细胞上分离，以验证巨噬细胞TF-PAR2信号传导有助于脂肪炎症和胰岛素耐药性。在AIM 3中，我们将表征抗TF治疗策略在逆转肥胖和胰岛素抵抗方面的机制和功效。评估单克隆抗体在表达人TF的转基因小鼠中有选择地抑制直接TF-VIIA-PAR2信号传导的作用，将确定这种策略的治疗潜力，该策略的伴随着出血并发症的最小风险。这些研究将为TF信号在肥胖症中的作用提供基本见解，并在这些途径中测试一种创新的治疗方法，以改善肥胖的代谢并发症。