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

建立慢性炎症凝血信号传导的遗传模型

• 批准号: 7933941
• 负责人: WOLFRAM RUF
• 金额: $ 48.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933941
• 关键词: Acute; Address; Animal Model; Anticoagulants; Area; Attenuated; Autoimmune Diseases; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Coagulation Process; Data; Development; Disease; Evaluation; Event; Generations; Genetic; Genetic Models; Hemostatic Agents; Human; Immune; Inflammation; Inflammatory; Knock-in Mouse; Knock-out; Limb structure; Malignant Neoplasms; Mediating; Mouse Strains; Obesity; PAR-2 Receptor; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Point Mutation; Process; Reaction; Relative (related person); Research; Resources; Role; Signal Pathway; Signal Transduction; Specificity; System; Technology; Testing; Therapeutic; Thrombin; Thrombin Receptor; Transgenic Animals; Vascular Endothelium; base; clinical application; genetic resource; human disease; in vivo; inhibitor/antagonist; innovation; insight; mouse model; novel; novel therapeutic intervention; prevent; public health relevance; receptor; response; success; tool

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域06：使能技术和特定的挑战主题06-HL-105：开发为理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、蛋白酶特异性抗凝药物正在进入临床应用，但我们对这些药物如何减弱心血管疾病、肥胖症、自身免疫性疾病和癌症中的炎症过程还不完全了解。近年来，对凝血蛋白酶信号在急性炎症中的作用的研究取得了新的进展。然而，这些途径在慢性炎症中的评价受到缺乏全面的基因敲入小鼠模型，专门探测凝血信号的阻碍。基于我们最近成功地选择性消融肢体内的凝血酶受体介导的凝血信号反应的网络，我们在这里提出了一个新的策略，将产生一组扩大的小鼠品系，以评估其他凝血蛋白酶的信号特异性。这项有针对性的短期研究提供了一个机会，可以生成工具，使人们能够对凝血蛋白酶在慢性炎症中的作用有一个新的理解水平，并推进关于蛋白酶选择性治疗如何干扰疾病中这些信号网络的创新研究。慢性炎症是导致高度流行的心血管和其他疾病的发展。止血系统通过改变血管内皮和免疫细胞功能的细胞信号传导事件来微调炎症反应。凝血蛋白酶信号传导的遗传模型的全面库将能够测试创新的治疗策略，以中断由慢性炎症引起的各种疾病过程。 公共卫生相关性：慢性炎症是导致高度流行的心血管疾病和其他疾病的原因。止血系统通过改变血管内皮和免疫细胞功能的细胞信号传导事件来微调炎症反应。凝血蛋白酶信号传导的遗传模型的全面库将能够测试创新的治疗策略，以中断由慢性炎症引起的各种疾病过程。