Senior Research Career Scientist

高级研究职业科学家

• 批准号: 10749218
• 负责人: Jeffrey R Capadona
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2030-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749218
• 关键词: Activities of Daily Living; Affect; American; Amputees; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Antioxidants; Area; Attenuated; Basic Science; Bathing; Behavior; Belief; Biocompatible Materials; Biological; Blood; Brain; Caregivers; Cells; Cellular immunotherapy; Central Nervous System; Cervical; Cervical spinal cord injury; Chemistry; Chronic; Clinical; Computers; Corrosives; Dedications; Deep Brain Stimulation; Detection; Devices; Disabled Persons; Disease; Electrodes; Engineering; Enzymes; Failure; Feces; Genes; Geometry; Goals; Government; Healthcare; Immunity; Implant; Individual; Infiltration; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Innate Immune System; Institution; Investigation; Journals; Laboratories; Life Expectancy; Limb Prosthesis; Liquid substance; Literature; Longevity; Lower Extremity; Manuscripts; Mechanics; Mediating; Methods; Microelectrodes; Military Personnel; Mission; Modeling; Modulus; Molecular; Motion; Movement; Muscle; Names; Nanotechnology; Natural Immunity; Nature; Nerve Degeneration; Neurons; Neurosciences; Outcome; Oxidative Stress; Paralysed; Pathologic; Pathway interactions; Patients; Peer Review; Performance; Persons; Pharmaceutical Preparations; Polymers; Privatization; Process; Proteins; Publishing; Quadriplegia; Quality of life; Recovery; Rehabilitation therapy; Reporting; Research; Research Personnel; Resolution; Ribosomal RNA; Robotics; Role; Science; Scientist; Seizures; Self-Help Devices; Seminal; Services; Shunt Device; Signal Transduction; Specificity; Spinal cord injury; Spinal cord injury patients; Sterility; Stream; Stroke; System; Technology; Therapeutic; Thinking; Time; Tissues; Translating; Upper Extremity; Ventricular; Veterans; Work; arm; biomacromolecule; blood-brain barrier crossing; brain computer interface; brain health; brain machine interface; brain tissue; career; clinical application; communication device; disability; experience; falls; feeding; gene therapy; gut microbiome; implantable device; implantation; improved; indexing; injured; interest; limb loss; materials science; mechanical device; metallicity; microbiome; mimetics; multidisciplinary; nervous system disorder; neural; neuroinflammation; neuroprotection; neurotransmission; pre-clinical; response; spatiotemporal; Activities of Daily Living; Affect; American; Amputees; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Antioxidants; Area; Attenuated; Basic Science; Bathing; Behavior; Belief; Biocompatible Materials; Biological; Blood; Brain; Caregivers; Cells; Cellular immunotherapy; Central Nervous System; Cervical; Cervical spinal cord injury; Chemistry; Chronic; Clinical; Computers; Corrosives; Dedications; Deep Brain Stimulation; Detection; Devices; Disabled Persons; Disease; Electrodes; Engineering; Enzymes; Failure; Feces; Genes; Geometry; Goals; Government; Healthcare; Immunity; Implant; Individual; Infiltration; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Innate Immune System; Institution; Investigation; Journals; Laboratories; Life Expectancy; Limb Prosthesis; Liquid substance; Literature; Longevity; Lower Extremity; Manuscripts; Mechanics; Mediating; Methods; Microelectrodes; Military Personnel; Mission; Modeling; Modulus; Molecular; Motion; Movement; Muscle; Names; Nanotechnology; Natural Immunity; Nature; Nerve Degeneration; Neurons; Neurosciences; Outcome; Oxidative Stress; Paralysed; Pathologic; Pathway interactions; Patients; Peer Review; Performance; Persons; Pharmaceutical Preparations; Polymers; Privatization; Process; Proteins; Publishing; Quadriplegia; Quality of life; Recovery; Rehabilitation therapy; Reporting; Research; Research Personnel; Resolution; Ribosomal RNA; Robotics; Role; Science; Scientist; Seizures; Self-Help Devices; Seminal; Services; Shunt Device; Signal Transduction; Specificity; Spinal cord injury; Spinal cord injury patients; Sterility; Stream; Stroke; System; Technology; Therapeutic; Thinking; Time; Tissues; Translating; Upper Extremity; Ventricular; Veterans; Work; arm; biomacromolecule; blood-brain barrier crossing; brain computer interface; brain health; brain machine interface; brain tissue; career; clinical application; communication device; disability; experience; falls; feeding; gene therapy; gut microbiome; implantable device; implantation; improved; indexing; injured; interest; limb loss; materials science; mechanical device; metallicity; microbiome; mimetics; multidisciplinary; nervous system disorder; neural; neuroinflammation; neuroprotection; neurotransmission; pre-clinical; response; spatiotemporal

Overall goals: My laboratory strives to understand and facilitate the neuroinflammatory response to all implanted devices within the central nervous system. Such devices range from ventricular shunts to various types of stimulating and recording electrodes. However, most of my efforts have been on intracortical microelectrodes due to their significance in research to understand the brain and the role in rehabilitative applications of Brain Computer Interfacing, which is of particular interest to the VA. By understanding mechanism of failure, we can pursue both materials-based and therapeutic-based methods to mitigate the inflammatory-mediated failure. 1) Role of tissue/device mechanical mismatch in microelectrode failure. We developed biologically inspired materials for intracortical microelectrodes to independently examine and manipulate device modulus, geometry, and drug-eluting capabilities. We have demonstrated that mechanically dynamic intracortical microelectrodes are stiff enough to be inserted into the brain, become compliant to reduce micro-motion and inhibit late-stage neuroinflammatory responses, can be fabricated into functional intracortical microelectrodes, and can be utilized to deliver anti-inflammatory therapeutics from the device substrate or in combination with microfluid devices. 2) Role of oxidative stress in microelectrode failure. Oxidative pathways have been implicated in both neurodegeneration and corrosive damage to both the metallic and insulating materials of current intracortical microelectrode technologies. Thus, approaches to mitigate or attenuate the deleterious effects of oxidative inflammatory products are of significant importance. We have demonstrated that several antioxidants can be delivered systemically or locally to temporally mitigate neuronal damage and loss, and that bioactive coatings with mimetic anti-oxidative enzymes can prolong neuroprotection and improve recording performance. 3) Role of specific immunity pathways in microelectrode failure. Pathological assessment of the neuroinflammatory response to intracortical microelectrodes has been limited to a dozen or so known neuroinflammatory proteins. We are using spatially resolved omics to developed one of the most comprehensive analyses to date the microelectrode/tissue interface. By identifying genes and proteins of interest, we can then explore hypotheses about specific innate immune systems or develop gene therapies for immune cell silencing. 4) Role of gut microbiome in microelectrode failure. Microbiome may play a role in modulating neuroinflammation. Constituents of the gut microbiome can directly infiltrate the brain causing a local inflammatory response, or act indirectly via metabolites or inflammatory factors that enter the blood stream and cross the blood brain barrier. We utilized 16S rRNA analysis to show that the composition of gut-resident microbiome in feces and brain tissue changes following microelectrode implantation and can be modulated through treatment to impact the quality of chronic intracortical recordings. We seek to translate these findings from preclinical to clinical therapies to improve microelectrode performance.

总体目标：我的实验室努力理解和促进对所有植入的神经炎症反应 中枢神经系统中的设备。这样的设备范围从心室分流到各种类型 刺激和记录电极。但是，我的大部分努力都是在皮质内微电极上 由于它们在研究中了解大脑和大脑康复应用中的作用的重要性 计算机接口，这是VA特别感兴趣的。通过了解失败机制，我们可以 采用基于材料和基于治疗的方法来减轻炎症介导的衰竭。 1）组织/装置机械不匹配在微电极故障中的作用。我们开发了受生物学启发的 物质内微电极独立检查和操纵装置模量，几何形状， 和洗脱功能。我们已经证明了机械动态的皮质内微电极 足够僵硬以插入大脑，变得合规以减少微动并抑制后期 神经炎症反应，可以制造成功能性的物质内微电极，并且可以使用 从设备基材或与微流体设备结合使用抗炎治疗剂。 2）氧化应激在微电极衰竭中的作用。氧化途径都与 神经变性和腐蚀性损伤对当前物质内的金属和绝缘材料均 微电极技术。因此，减轻或衰减氧化的有害作用的方法 炎症产品至关重要。我们已经证明了几种抗氧化剂可以是 全身或本地交付，以减轻神经元损害和损失，并进行生物活性涂层 使用模拟抗氧化酶可以延长神经保护作用并改善记录性能。 3）特异性免疫途径在微电极故障中的作用。病理评估 神经炎症对心脏内微电极的反应已限于十几个或已知的 神经炎症蛋白。我们正在使用空间解决的OMIC来开发最全面的之一 分析与微电极/组织界面有关。通过识别感兴趣的基因和蛋白质，我们可以 探索有关特定先天免疫系统或开发用于免疫细胞沉默的基因疗法的假设。 4）肠道微生物组在微电极故障中的作用。微生物组可能在调节中发挥作用 神经炎症。肠道微生物组的成分可以直接浸润大脑，从而导致局部 炎症反应，或通过进入血液的代谢产物或炎症因子间接起作用 越过血脑屏障。我们利用16S rRNA分析表明肠道居民的组成 微电极植入后粪便和脑组织的微生物组变化，可以调节 通过治疗以影响慢性心脏记录的质量。我们试图翻译这些发现 从临床前疗法到临床疗法，以提高微电极性能。