Elucidating Structural and Functional Alterations of CNS Pericytes on Chronic Brain Implants

阐明慢性脑植入物中中枢神经系统周细胞的结构和功能改变

• 批准号: 10700794
• 负责人: Steven Wellman
• 金额: $ 3.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700794
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid Proteins; Animals; Area; Automobile Driving; Award; Back; Behavior; Biological; Biology; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Diseases; Brain Injuries; Brain Pathology; Calcium; Calcium Signaling; Cell Death; Cell Line; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cessation of life; Chronic; Clinical; Data; Depreciation; Deterioration; Devices; Disabled Persons; Disease; Disease Pathway; Disease Progression; DsRed; Electrodes; Electrophysiology (science); Encephalitis; Equipment Malfunction; Etiology; Face; Failure; Fellowship; Foreign Bodies; Functional disorder; Future; Goals; Halorhodopsins; Health; Histology; Homeostasis; Implant; Injury; Interruption; Knowledge; Light; Link; Mediating; Mediator of activation protein; Mentors; Methodology; Microelectrodes; Modeling; Molecular; Morphology; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuroimmune; Neurons; Neurosciences; Outcome; Pathogenesis; Pathology; Patients; Pattern; Performance; Perfusion; Pericytes; Phase; Physiological; Play; Process; Reaction; Relaxation; Research; Research Personnel; Research Project Grants; Role; Scheme; Secure; Sensory; Structure; Techniques; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Transgenic Model; United States National Institutes of Health; Vascular Diseases; Viral; Work; angiogenesis; calcium indicator; career; career development; cerebrovascular health; clinical application; combat; constriction; design; experimental study; glial activation; implantation; improved; in vivo; innovation; multiphoton imaging; nervous system disorder; neural implant; neuroinflammation; neuron loss; neuropathology; neuroprotection; neuroregulation; neurotechnology; neurotransmission; neurovascular; neurovascular unit; novel; optogenetics; post-doctoral training; relating to nervous system; repaired; response; skills; spatiotemporal; stem; tau-1; tool; two photon microscopy; vascular injury

PROJECT SUMMARY Penetrating microelectrodes significantly advance our understanding of brain function and enable us to restore motor and sensory control lost from neurological disorders. However, the efficacy of intracortical microelectrodes for clinical therapy is limited by an inability to detect or modulate neurons over time and is presumed to be due to severe bodily reactions to a foreign body. While the biological mechanisms regulating device failure are poorly understood, emerging hypotheses suggests that neurovascular dysfunction plays a significant role in enabling progressive neuron loss and tissue failure after device implantation. Neurovascular health and function are governed in part by perivascular pericytes, specialized mural cells in direct apposition with cerebral blood vessels. Pericytes demonstrate important roles regulating vascular tone, blood-brain barrier integrity, and neuroimmune functions and have become increasingly recognized as prominent figures in the pathogenesis of brain inflammation and disease. How device implantation disrupts the structure and function of pericytes and the subsequent ramifications on neural health, glial activity, and vascular integrity are currently unknown. Preliminary data suggests that device insertion alters the distribution and morphology of pericytes, which occurs in tandem with neuronal calcium dysfunction, glial activation, and vascular deterioration. For the F99 phase, I will determine how electrode implantation affects functional pericyte activity in vivo using a genetically encoded calcium indicator GCaMP6s to characterize calcium signaling dynamics exclusively within PDGFRβ+ pericyte cells. Additionally, I will train in the use of optogenetics to target and modulate pericyte-specific responses during insertion and throughout implantation with the expected outcome of promoting pericyte health, neuroprotection, and vascular function after brain injury. Adeno-associated viral (AAV) transduction will be performed to visualize neuronal calcium dynamics following pericyte stimulation. Finally, substantial fellowship efforts will focus on activities in professional career development in anticipation of securing postdoctoral training during the K00 phase. For the K00 phase, I will leverage my expertise of neural interface technology and neuroimmune responses to continue identifying and characterizing mechanisms of neurodegeneration during brain injury and use advanced neuromodulating techniques to treat or reverse pathology in brain diseases such as Alzheimer’s disease and related dementia (ADRD). Activities during this phase will involve more directed career development training that is tailored toward becoming a fully realized, independent ADRD investigator. In summary, completion of the above-mentioned research aims and professional training backed by the generous support of an NIH D-SPAN award will enable me to carve out a novel and innovative area of research at the intersect of neural interface biology, neuromodulation, and neurodegenerative disease.

项目摘要 穿透性微电极大大推进了我们对大脑功能的理解，使我们能够 恢复因神经系统疾病而失去的运动和感觉控制。然而，皮质内注射的有效性 用于临床治疗的微电极受到不能随时间检测或调节神经元的限制， 推测是由于对异物的严重身体反应。虽然生物机制调节 设备故障知之甚少，新兴的假设表明，神经血管功能障碍发挥了重要作用， 在装置植入后能够进行性神经元损失和组织衰竭中起重要作用。神经血管 健康和功能部分由血管周细胞（直接并置的特化壁细胞）控制 脑血管的问题周细胞在调节血管张力、血脑屏障、 完整性和神经免疫功能，并已越来越多地被认为是在 脑炎症和疾病的发病机制。器械植入如何破坏组织结构和功能 周细胞及其对神经健康、神经胶质活性和血管完整性的后续影响， 未知初步数据表明，装置插入改变了周细胞的分布和形态， 其与神经元钙功能障碍、神经胶质活化和血管恶化同时发生。 对于F99阶段，我将确定电极植入如何影响体内功能性周细胞活性 使用遗传编码的钙指示剂GCaMP 6s来表征钙信号传导动力学 仅在PDGFRβ+周细胞内。此外，我将训练使用光遗传学来靶向和 在插入期间和整个植入过程中调节周细胞特异性反应，获得预期结果 促进周细胞健康，神经保护和脑损伤后的血管功能。腺相关病毒 (AAV)进行转导以观察周细胞刺激后的神经元钙动力学。 最后，大量的研究金努力将侧重于预期的专业职业发展活动， 在K 00阶段确保博士后培训。 对于K 00阶段，我将利用我在神经接口技术和神经免疫方面的专业知识， 响应继续识别和表征脑损伤期间神经变性的机制， 使用先进的神经调节技术来治疗或逆转阿尔茨海默氏症等脑部疾病的病理 疾病和相关痴呆症（ADRD）。这一阶段的活动将涉及更多的定向职业 发展培训是为了成为一个完全实现的，独立的ADRD研究者。在 总结，完成上述研究目标和专业培训的慷慨支持 一个NIH D-SPAN奖的支持将使我能够开拓一个新的和创新的研究领域， 神经界面生物学、神经调节和神经退行性疾病交叉。