Mechanisms of Fibrin Action in Neuronal Functions

纤维蛋白在神经元功能中的作用机制

• 批准号: 8815340
• 负责人: Katerina Akassoglou
• 金额: $ 23.88万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815340
• 关键词: Affect; Animal Model; Attenuated; Binding; Blood - brain barrier anatomy; Blood Proteins; Blood Vessels; Blood coagulation; Brain; Cells; Cognitive; Cognitive deficits; Data; Dendrites; Dendritic Spines; Deposition; Disease; Event; Experimental Designs; Extravasation; Fibrin; Fibrinogen; Functional disorder; Genetic; Goals; HIV; HIV Encephalopathy; Hemorrhage; Human; ITGAM gene; ITGB2 gene; Image; Immune response; Impaired cognition; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Integrins; Intervention; Ischemia; Knockout Mice; Lasers; Life; Link; Mediating; Memory impairment; Microglia; Microscopy; Modeling; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Paralysed; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Plasma; Play; Process; Protocols documentation; Regulation; Risk; Risk Factors; Role; Rupture; Schizophrenia; Signal Transduction; Spinal Cord; Stroke; Study models; Testing; Therapeutic; Time; Transgenic Mice; Traumatic Brain Injury; Vertebral column; Work; cerebrovascular; density; dentate gyrus; design; drug efficacy; drug testing; immune activation; in vivo; memory recall; molecular pathology; nervous system disorder; neuroinflammation; neuron loss; neurotoxicity; normal aging; novel; pharmacodynamic model; promoter; public health relevance; receptor; repaired; response; spatial memory; therapeutic development; two-photon

DESCRIPTION (provided by applicant): Patients with central nervous system pathologies, including multiple sclerosis, stroke, spinal cord and traumatic injuries, often present with cognitive impairment, indicative of neuronal dysfunction. Although vascular damage and blood-brain barrier (BBB) disruption, which results in leakage of blood proteins into the brain parenchyma, are hallmarks of cognitive pathologies, the molecular links between BBB disruption and neuronal dysfunction remain poorly understtod. We have shown that CNS deposition of fibrinogen, a critical component of blood coagulation, is not merely a marker of BBB disruption, but plays a causative role in the regulation of inflammation and repair in the CNS by activating integrin receptors expressed in nervous system cells. Our long-term goal is to characterize the molecular pathways that are responsible for the effects of fibrinogen in nervous system pathogenesis, as a prerequisite for the development of therapeutic protocols that can specifically target the interactions between fibrinogen and its receptors and attenuate neuropathological disease processes. Our major hypothesis is that fibrinogen activates the CNS innate immune response to induce spine alterations and cognitive deficits in nervous system pathology. Our preliminary data demonstrate that a) stereotactic injection of fibrinogen into the dentate gyrus induces microglial activation and impairs memory recall, b) injection of fibrinogen induces neuronal loss, dendrite retraction and dendritic spine density reduction in mice as shown with in vivo two-photon microscopy, and c) genetic depletion of the CD11b/CD18 microglial receptor rescues fibrinogen-induced spine elimination and dendritic retraction. Our specific aims are designed to test our working model, in which fibrinogen, deposited in the brain following BBB disruption and cerebrovascular abnormalities, activates the innate immune response and causes spine elimination and cognitive decline. We employ a cutting edge experimental design that includes in vivo two-photon imaging of neurons in transgenic mice expressing YFP under Thy1 promoter, following the dynamic interactions between microglial and spines over time in the living mouse, and pharmacologic and genetic inhibition of innate immune activation, including specific inhibition of fibrinogen interactions with CD11b that do not affects its beneficial functions in blood coagulation. Identifying the molecular interplay between fibrinogen following BBB disruption, activation of innate immunity, and neurotoxicity could potentially provide specific targets for pharmacological intervention in a variety of diseases characterized by cerebrovascular abnormalities or increased BBB permeability and cognitive impairment.

描述（由申请人提供）：患有中枢神经系统病变的患者，包括多发性硬化症、中风、脊髓和创伤性损伤，通常存在认知障碍，表明神经元功能障碍。虽然血管损伤和血脑屏障（BBB）破坏（其导致血液蛋白渗漏到脑实质中）是认知病理学的标志，但BBB破坏和神经元功能障碍之间的分子联系仍然知之甚少。我们已经表明，CNS中纤维蛋白原的沉积，血液凝固的关键组成部分，不仅是血脑屏障破坏的标志物，但通过激活神经系统细胞中表达的整合素受体，在炎症的调节和CNS修复中起着致病作用。我们的长期目标是表征负责纤维蛋白原在神经系统发病机制中的作用的分子途径，作为开发可以特异性靶向纤维蛋白原及其受体之间的相互作用并减弱神经病理性疾病过程的治疗方案的先决条件。我们的主要假设是，纤维蛋白原激活中枢神经系统先天性免疫反应，诱导脊柱改变和神经系统病理认知缺陷。我们的初步数据表明，a）立体定向注射纤维蛋白原到齿状回诱导小胶质细胞活化和损害记忆回忆，B）注射纤维蛋白原诱导神经元丢失，树突回缩和树突棘密度减少小鼠体内双光子显微镜显示，和c）遗传消耗的CD 11 B/CD 18小胶质细胞受体挽救纤维蛋白原诱导的棘消除和树突回缩。我们的具体目标旨在测试我们的工作模型，其中血脑屏障破坏和脑血管异常后沉积在大脑中的纤维蛋白原激活先天免疫反应并导致脊柱消除和认知能力下降。我们采用了一种尖端的实验设计，包括在体内双光子成像的转基因小鼠中的神经元表达YFP下Thy 1启动子，随着时间的推移，在活的小鼠中小胶质细胞和棘之间的动态相互作用，以及先天免疫激活的药理学和遗传学抑制，包括特异性抑制纤维蛋白原与CD 11b的相互作用，不影响其在血液凝固中的有益功能。确定血脑屏障破坏、先天免疫激活和神经毒性后纤维蛋白原之间的分子相互作用，可能为以脑血管异常或血脑屏障通透性增加和认知障碍为特征的各种疾病的药物干预提供特异性靶点。