Toward a Repertoire of Genetic Models for Coagulation Signaling in Chronic Inflam

描述(由申请人提供)：本申请涉及广泛的挑战领域06：使能技术和特定挑战主题06-HL-105：开发可为了解人类慢性炎症提供信息的转基因动物模型。新一代高选择性、特定于蛋白水解酶的抗凝血药正在进入临床应用，但我们对这些药物如何减轻心血管疾病、肥胖、自身免疫性疾病和癌症的炎症过程的了解还不完全。最近在了解凝血酶信号在急性炎症中的作用方面取得了进展。然而，由于缺乏一套全面的敲入小鼠模型来专门探测凝血信号，对这些途径在慢性炎症中的评估一直受到阻碍。基于我们最近成功地有选择地消融凝血酶受体介导的凝血信号反应网络中的肢体，我们提出了一种新的策略，该策略将产生一组扩大的小鼠品系来评估其他凝血酶的信号特异性。这项有针对性的短期研究提供了一个机会来产生工具，这些工具将使人们能够更好地理解凝血酶在慢性炎症中的作用，并推进关于蛋白酶选择性疗法如何干扰疾病中的这些信号网络的创新研究。慢性炎症正在导致高度流行的心血管疾病和其他疾病的发展。止血系统通过细胞信号事件微调炎症反应，改变血管内皮细胞和免疫细胞的功能。一套全面的凝血酶信号遗传模型将能够测试创新的治疗策略，以中断由慢性炎症引发的各种疾病过程。 与公共卫生的相关性：慢性炎症正在促进高度流行的心血管疾病和其他疾病的发展。止血系统通过细胞信号事件微调炎症反应，改变血管内皮细胞和免疫细胞的功能。一套全面的凝血酶信号遗传模型将能够测试创新的治疗策略，以中断由慢性炎症引发的各种疾病过程。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 06: Enabling Technologies and the specific Challenge Topic 06-HL-105: Develop transgenic animal models that are informative for understanding chronic inflammation in humans. A new generation of highly selective, protease-specific anticoagulant drugs is entering clinical applications, but we have an incomplete understanding of how these drugs attenuate inflammatory processes in cardiovascular diseases, obesity, autoimmune disorders and cancer. There has been recent progress in understanding the role of coagulation protease signaling in acute inflammation. However, the evaluation of these pathways in chronic inflammation has been hampered by the lack of a comprehensive repertoire of knock-in mouse models that specifically probe coagulation signaling. Based on our recent success to selectively ablate limbs within the network of coagulation signaling responses mediated by the thrombin receptor, we here propose a new strategy that will generate an expanded set of mouse strains to evaluate the signaling specificity of other coagulation proteases. This targeted short term research provides an opportunity to generate tools that will enable a new level of understanding of the role of coagulation proteases in chronic inflammation and advance innovative research on how protease-selective therapeutics interfere with these signaling networks in disease. Chronic inflammation is contributing to the development of highly prevalent cardiovascular and other diseases. The hemostatic system is fine tuning inflammatory reactions by cell signaling events that change the function of the vascular endothelium as well as immune cells. A comprehensive repertoire of genetic models for coagulation protease signaling will enable testing of innovative therapeutic strategies to interrupt diverse disease processes that are fueled by chronic inflammation. PUBLIC HEALTH RELEVANCE: Chronic inflammation is contributing to the development of highly prevalent cardiovascular and other diseases. The hemostatic system is fine tuning inflammatory reactions by cell signaling events that change the function of the vascular endothelium as well as immune cells. A comprehensive repertoire of genetic models for coagulation protease signaling will enable testing of innovative therapeutic strategies to interrupt diverse disease processes that are fueled by chronic inflammation.