Mechanisms Linking Hemostatic Facotrs to Neuroinflammatory Disease

止血因子与神经炎症疾病的联系机制

• 批准号: 8190011
• 负责人: Eric S Mullins
• 金额: $ 13.11万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190011
• 关键词: Adult; Alleles; Alzheimer' s Disease; Antisense Oligonucleotides; Autoimmune Process; Automobile Driving; Award; Binding; Blood - brain barrier anatomy; Blood Coagulation Factor; Blood Vessels; Bone Marrow; Cell Lineage; Cell physiology; Central Nervous System Diseases; Chemicals; Clinical; Complement; Coupled; Coupling; Data; Demyelinating Diseases; Demyelinations; Deposition; Development; Development Plans; Disease; Disease Progression; Exhibits; Experimental Autoimmune Encephalomyelitis; Extravasation; Fibrin; Fibrinogen; Foundations; Funding; GTP-Binding Proteins; Gene Targeting; Generations; Genetic; Hemostatic Agents; Hemostatic function; Hepatic; Human; In Vitro; Inflammation; Inflammatory; Integrins; Knock-out; Lead; Lesion; Leukocytes; Link; Liver; Mediating; Mentors; Messenger RNA; Microglia; Motor; Multiple Sclerosis; Mus; Mutation; Neuraxis; Neurologic Deficit; PAR-1 Receptor; Paralysed; Pathology; Patients; Pharmacia brand of estropipate; Physicians; Process; Protein C; Proteinase-Activated Receptors; Proteolysis; Prothrombin; Receptor Signaling; Research; Role; Scientist; Seminal; Severity of illness; Signal Transduction; Specificity; Substrate Specificity; Symptoms; System; Testing; Thrombin; Time; base; career development; cell type; cellular targeting; defined contribution; disorder control; in vivo; innovation; monocyte; mouse model; mutant; neuroinflammation; novel; novel therapeutics; programs; receptor; skills; tool

DESCRIPTION (provided by applicant): The long-term objective of this research program is to better understand the mechanisms that couple hemostatic factors in general, and thrombin in particular, to neuroinflammatory disease (e.g., multiple sclerosis). Our central hypothesis is that thrombin and thrombin-mediated proteolysis is a critical regulator of inflammation tied to central nervous system (CNS) inflammatory disease and is mechanistically linked to the progression of inflammation and demyelination. This hypothesis is supported by strong preliminary data that suggests thrombin is integrally associated with the development of neurologic deficits associated with experimental autoimmune encephalomyelitis (EAE), an experimental setting for neuroinflammatory disease. The seminal finding that thrombin is a critical modifier of CNS inflammatory disease points to several possible fibrin (ogen)-dependent and -independent mechanisms coupling hemostatic factors to inflammation. The contribution of thrombin to CNS microglial activation and vascular leak will be established in the setting of EAE through the use of two complementary approaches: a) diminution of circulating prothrombin by use of an anti- sense oligonucleotide (ASO) gap-mer; and b) the use of a novel mouse line expressing a mutant form of prothrombin with a substrate specificity switch favoring protein C over prothrombotic substrates (Aim 1). The mechanism(s) coupling thrombin-mediated proteolysis to neuroinflammation will be further investigated by examining the role of protease activated receptor 1 (PAR-1) to the progression of paralysis associated with EAE in mice that lack PAR-1. Furthermore, the specific cell types in which PAR-signaling supports neuroinflammatory disease and loss of motor function will be determined by using a novel and only recently established mouse line carrying a "floxed" conditional PAR-1 knockout allele (Aim 2). These proposed studies will provide a mechanistic understanding of the cross-talk between the hemostatic and inflammatory systems in neuroinflammatory disease. These studies may also provide the fundamental foundation for novel therapeutic strategies to limit the progression of MS and other common forms of CNS disease, including Alzheimer's disease. Furthermore, the applicant will benefit from the protected, mentored time of this K08 award while pursuing studies that are an ideal platform for transitioning to independence. Through the career development plan outlined in this project, the applicant will build a record of accomplishment with a significant and novel research niche while refining the skills and tools necessary to succeed as an independent R01-funded physician-scientist. PUBLIC HEALTH RELEVANCE: Project Narrative Multiple sclerosis is a severe debilitating neuroinflammatory disease that affects 250,000-350,000 in the United States and millions worldwide. This research program is focused on understanding the mechanisms that link hemostatic factors to the progression of neurologic deficits in neuroinflammation. The knowledge gained from this research may enable investigation into new modalities of therapy. Novel hemostasis- based therapies would provide treatment options for this disease process other than the current immunosuppressive regimens.

描述（由申请人提供）：该研究计划的长期目标是更好地了解一般止血因子（特别是凝血酶）与神经炎症疾病（例如多发性硬化症）的耦合机制。我们的中心假设是，凝血酶和凝血酶介导的蛋白水解是与中枢神经系统（CNS）炎症性疾病相关的炎症的关键调节因子，并且在机制上与炎症和脱髓鞘的进展相关。这一假设得到了强有力的初步数据的支持，这些数据表明凝血酶与实验性自身免疫性脑脊髓炎（EAE）（一种神经炎症疾病的实验环境）相关的神经功能缺陷的发展密切相关。凝血酶是中枢神经系统炎症性疾病的关键调节剂这一开创性发现指出了几种可能的纤维蛋白（原）依赖性和非依赖性机制，将止血因子与炎症耦合起来。凝血酶对 CNS 小胶质细胞激活和血管渗漏的贡献将通过使用两种互补的方法在 EAE 中确定：a) 通过使用反义寡核苷酸 (ASO) 缺口聚体减少循环凝血酶原； b) 使用表达突变型凝血酶原的新型小鼠品系，其底物特异性开关有利于蛋白 C 而不是促血栓底物（目标 1）。将通过检查蛋白酶激活受体 1 (PAR-1) 在缺乏 PAR-1 的小鼠中与 EAE 相关的瘫痪进展中的作用，进一步研究凝血酶介导的蛋白水解与神经炎症的耦合机制。此外，将通过使用新近建立的携带“floxed”条件性 PAR-1 敲除等位基因的新型小鼠品系来确定 PAR 信号传导支持神经炎症性疾病和运动功能丧失的特定细胞类型（目标 2）。这些拟议的研究将为神经炎症疾病中止血系统和炎症系统之间的相互作用提供机制上的理解。这些研究还可能为限制多发性硬化症和其他常见中枢神经系统疾病（包括阿尔茨海默病）进展的新治疗策略提供基础。此外，申请人将受益于 K08 奖项的受保护和指导时间，同时继续学习，这是过渡到独立的理想平台。通过该项目中概述的职业发展计划，申请人将在重要且新颖的研究领域建立成就记录，同时完善作为独立 R01 资助的医师科学家取得成功所需的技能和工具。 公共健康相关性：项目叙述 多发性硬化症是一种严重的神经炎症性疾病，影响美国 250,000-350,000 人和全世界数百万人。该研究项目的重点是了解止血因素与神经炎症的神经缺陷进展之间的联系机制。从这项研究中获得的知识可能有助于研究新的治疗方式。除了目前的免疫抑制方案之外，新型止血疗法将为这种疾病过程提供治疗选择。