Effects of Iron Accumulation in Intracortical Implants and Protection by Iron Chelation

皮质内植入物中铁积累的影响和铁螯合的保护

• 批准号: 10657932
• 负责人: Abhishek Prasad
• 金额: $ 61.55万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657932
• 关键词: Acute; Blood Vessels; Brain; Brain Injuries; Catalysis; Cell Survival; Cells; Cerebral hemisphere hemorrhage; Chelating Agents; Chelation Therapy; Chemicals; Chemistry; Chronic; Clinical; DNA biosynthesis; Data Set; Deep Brain Stimulation; Electric Stimulation; Electrodes; Electrophysiology (science); Epilepsy; Erythrocytes; Event; Failure; Foreign Bodies; Free Radicals; Future; Gene Expression; Gilles de la Tourette syndrome; Goals; Heme; Hemoglobin; Human; Hydrogels; Immunohistochemistry; Implant; Implanted Electrodes; Inflammation; Inflammatory; Injury; Ions; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Knowledge; Literature; Mediating; Metabolism; Metals; Methods; Microelectrodes; Microglia; Modeling; Molecular Target; Motor; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurologic; Neurons; Outcome; Oxidative Stress; Paralysed; Parkinson Disease; Pathway interactions; Patients; Performance; Persons; Pharmaceutical Preparations; Physiological; Play; Process; Proteomics; Publishing; Quantitative Reverse Transcriptase PCR; Reaction; Reporting; Research; Resolution; Role; Route; Secondary to; Series; Signal Transduction; Site; Slice; Stroke; Surface; Techniques; Therapeutic; Thick; Tissues; Trauma; Traumatic Brain Injury; Wallerian Degeneration; Work; blood-brain barrier crossing; blood-brain barrier disruption; brain computer interface; brain parenchyma; brain tissue; cell injury; chelation; clinical application; disability; dosage; drug release profile; functional restoration; glial activation; immune activation; immune modulating agents; immunoregulation; implantation; improved; in vivo; iron chelation therapy; limb movement; materials science; metal chelator; neural; neural implant; neuroinflammation; neuron apoptosis; neuron loss; neurophysiology; neuroprosthesis; neuroregulation; neurotransmission; non-healing wounds; oxygen transport; protein expression; repaired; response; side effect; tool; transcriptomics

Microelectrodes (ME) implanted in the nervous system are critical tools for neurophysiological research and in clinical applications that use neuromodulation to treat motor-disability conditions. However, long term stability and functional performance are the critical barriers for implanted ME that have limited their use in clinical applications. Vascular disruption during ME implantation and their continued presence in the brain tissue leads to erythrocyte/hemoglobin entry in the brain parenchyma, which results in iron to be released and accumulated in the tissue. While iron is essential for various physiological functions, an overload of free iron contributes to oxidative and inflammatory mediated cell damage. Our central hypothesis is that iron accumulation in the brain tissue after ME implantation contributes towards chronic oxidative stress, microglial degeneration and neurodegeneration and thus, results in poor neural signal quality. Congruent with our findings, we also hypothesize that chelation of excess free iron can improve long-term functionality of implanted ME. The goal of this proposal is to develop an iron chelation approach, by using the iron chelator deferasirox (DFO), to mitigate the neuroinflammatory response to improve long-term performance of ME implanted in the brain. The study will use multiple techniques that include 1) transcriptomics (qRT-PCR) of the entire brain tissue harboring the ME to provide a macroscopic overview of ongoing inflammatory reactions and not just the tissue at the recording sites which is commonly reported in literature, 2) spatial transcriptomics and proteomics at recording sites, within the same tissue slice, to provide information at high spatial resolution, and 3) immunohistochemistry, all combined with electrophysiology, to produce a comprehensive dataset with readouts of both protein and gene expression in the brain tissue. Further, the study will use materials science and surface chemistry approaches to develop local chelation approach for modulating iron species at the electrode-tissue interface. Aim 1 will determine the effects of iron chelation on microglial degeneration and neurodegeneration and its impact on neuronal recordings. Systemic administration of immunomodulatory drugs is often not the best strategy as 1) drugs need to cross the BBB, which limits their availability at the injury site and 2) require large dosages, which has systemic side effects. Further, studies have shown metal chelators, if present in high concentration, lose their selectivity during systemic chelation therapy, resulting in homeostatic chemical imbalances in which other metal ions are depleted. These concerns provide the rationale to locally modulate the iron species at the electrode-tissue interface. Aim 2 will develop an iron chelator embedded hydrogel coating on ME for modulating excess free iron at the electrode-tissue interface. By studying the dynamics of iron accumulation, with and without chelation, in relation to other inflammation pathways simultaneously, the project has the potential to uncover potential signaling targets that can be immuno-modulated for improving long-term electrode function.

植入神经系统的微电极 (ME) 是神经生理学研究和其他领域的重要工具。 使用神经调节来治疗运动障碍的临床应用。但长期稳定性 和功能性能是植入式 ME 的关键障碍，限制了其在临床中的使用 应用程序。 ME 植入期间的血管破坏及其在脑组织中的持续存在导致 红细胞/血红蛋白进入脑实质，导致铁释放和积累 在组织中。虽然铁对于各种生理功能至关重要，但游离铁过多会导致 氧化和炎症介导的细胞损伤。我们的中心假设是大脑中铁的积累 ME 植入后的组织会导致慢性氧化应激、小胶质细胞变性和 神经退行性变，从而导致神经信号质量差。与我们的发现一致，我们还 假设过量游离铁的螯合可以改善植入 ME 的长期功能。目标是 该提案旨在开发一种铁螯合方法，通过使用铁螯合剂地拉罗司 (DFO)，以减轻 神经炎症反应，以改善植入大脑的 ME 的长期性能。该研究将 使用多种技术，包括 1) 包含 ME 的整个脑组织的转录组学 (qRT-PCR) 提供持续炎症反应的宏观概述，而不仅仅是记录时的组织 文献中常见的位点，2）记录位点的空间转录组学和蛋白质组学， 在同一组织切片内，以高空间分辨率提供信息，以及 3) 免疫组织化学，所有 与电生理学相结合，生成包含蛋白质和基因读数的综合数据集 脑组织中的表达。此外，该研究将使用材料科学和表面化学方法 开发局部螯合方法来调节电极-组织界面处的铁物种。目标1将 确定铁螯合对小胶质细胞变性和神经变性的影响及其对 神经元记录。免疫调节药物的全身给药通常不是最好的策略，因为 1) 药物需要穿过血脑屏障，这限制了它们在损伤部位的可用性；2）需要大剂量，这 有全身副作用。此外，研究表明，金属螯合剂如果以高浓度存在，会损失 它们在全身螯合治疗期间的选择性，导致稳态化学失衡，其中其他 金属离子被耗尽。这些问题为局部调节铁形态提供了理论基础。 电极-组织界面。 Aim 2 将在 ME 上开发一种嵌入铁螯合剂的水凝胶涂层，用于 调节电极-组织界面处过量的游离铁。通过研究铁积累的动态， 有或没有螯合，同时与其他炎症途径相关，该项目具有 有可能发现潜在的信号传导靶标，这些靶标可以通过免疫调节来改善长期症状 电极功能。