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

• 批准号: 8108442
• 负责人: FAHUMIYA SAMAD
• 金额: $ 61.91万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108442
• 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

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. PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions in the US, and with it there is an increasing rise in obesity-mediated health complications including insulin resistance, type 2 diabetes and cardiovascular disease. In spite of this, the molecular changes that promote these disorders are still poorly defined. Our research aims to understand the role played by tissue factor signaling via protease activated receptor-2, proteins involved in clotting and inflammation, in the pathogenesis of obesity and the metabolic syndrome.

描述（由申请人提供）：肥胖在西方社会已达到流行病的比例。然而，其病理机制尚未完全了解，治疗选择仍然有限。我们的目标是评估一种新的方法，抑制组织因子（TF）信号传导的抗体，在治疗肥胖和代谢综合征。除了其促凝血作用外，TF在炎症和血管生成中具有非凝血依赖性功能。因此，VIIa与TF的结合也导致通过G蛋白偶联的蛋白酶激活受体-2（PAR 2）的直接信号传导。高脂饮食（HFD）喂养的肥胖症C57 BL/6 J小鼠模型模拟人类状况，包括进食行为（摄食过多）、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。我们发现TF和PAR 2在脂肪组织（AT）中共表达，并且在HFD诱导的肥胖小鼠的脂肪组织中升高。此外，缺乏TF的胞质结构域的小鼠（TF 4CT小鼠）或PAR 2受到保护免于HFD诱导的肥胖和随后的胰岛素抗性的发展。在肥胖的野生型小鼠中，阻断TF-VIIa结合的抗体迅速改善胰岛素抵抗。当用特异性阻断TF信号传导的单克隆抗体治疗表达人TF的肥胖转基因小鼠时，胰岛素抵抗也得到改善。这项资助的总体目标是表征TF信号传导对肥胖发病机制的贡献，长期目标是推进该途径的合理药理学靶向，以对抗肥胖及其并发症。在目标1中，我们将使用野生型、TF 4CT、PAR 2-/-和双缺陷型TF 4CT/PAR 2-/-小鼠以及从这些敲除小鼠中分离的骨髓（BM）嵌合体和脂肪细胞来表征TF-VIIa-PAR 2信号传导支持肥胖症发展的贡献、细胞靶标和机制。在目标2中，我们将使用多种方法，包括TF 4CT和PAR 2-/-小鼠的BM嵌合体和分离的AT巨噬细胞，以验证巨噬细胞TF-PAR 2信号传导有助于脂肪炎症和胰岛素抵抗。在目标3中，我们将描述抗TF治疗策略逆转肥胖和胰岛素抵抗的机制和疗效。在表达人TF的转基因小鼠中评价选择性抑制直接TF-VIIa-PAR 2信号传导的单克隆抗体的作用将确定这种具有最小出血并发症风险的策略的治疗潜力。这些研究将为TF信号在肥胖中的作用提供基本见解，并测试这些途径中的创新治疗方法，以改善肥胖的代谢并发症。 公共卫生关系：肥胖在美国已达到流行病的程度，肥胖介导的健康并发症包括胰岛素抵抗、2型糖尿病和心血管疾病也在不断增加。尽管如此，促进这些疾病的分子变化仍然很难定义。我们的研究旨在了解组织因子信号通过蛋白酶激活受体-2（参与凝血和炎症的蛋白质）在肥胖和代谢综合征发病机制中的作用。