Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries

慢性与急性神经组织移植治疗 TBI 引起的皮质损伤

• 批准号: 10296334
• 负责人: HAN-CHIAO ISAAC CHEN
• 金额: $ 41.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296334
• 关键词: Acute; Acute Brain Injuries; Affect; Anatomy; Animals; Architecture; Brain; Cell Line; Cells; Cerebral cortex; Chronic; Chronic Phase; Cicatrix; Clinical; Cognitive deficits; Data; Development; Excision; Fluorescent Protein Tracings; Fostering; Future; Gliosis; Goals; Green Fluorescent Proteins; Health; Histologic; Histology; Human; In Vitro; Injury; Knowledge; Maintenance; Mission; National Institute of Neurological Disorders and Stroke; Nature; Neurologic Deficit; Neurons; Organoids; Outcome; Outcome Measure; Patients; Phase; Photic Stimulation; Process; Public Health; Rabies virus; Rattus; Recovery; Research; Sensory; Severities; Stroke; Structure; Synapses; System; Techniques; Testing; Therapeutic; Thinness; Tissue Transplantation; Tissues; Translations; Transplantation; Traumatic Brain Injury; Visual; Visual Cortex; brain circuitry; brain repair; cell replacement therapy; cohort; controlled cortical impact; disability; extracellular; functional outcomes; functional restoration; improved; improved outcome; in vivo; induced pluripotent stem cell; injured; innovation; nervous system disorder; novel strategies; optogenetics; organoid transplantation; personalized medicine; post-transplant; relating to nervous system; repair strategy; repaired; response; stem cells; tissue repair; translational approach; visual stimulus

PROJECT SUMMARY/ABSTRACT Injury to the cerebral cortex occurs frequently across the spectrum of severity in traumatic brain injury (TBI). No therapies exist to counter the neurological and cognitive deficits caused by these injuries, which are responsible for substantial disability after TBI. A promising strategy for restoring brain function after injury is cell replacement. Neural tissues that connect with host cortex locally and function as supplementary cortical processing modules are especially intriguing candidates for this approach. Currently available tissue substrates that are suitable for translation, including human brain organoids derived from patient-matched stem cell lines, do not fully recapitulate the architecture or micro-circuitry of cortex. However, they can still be used to investigate outstanding questions regarding neural tissue integration with the host brain. One essential issue that has not been examined systemically is the optimal timing of cell replacement after TBI. The overall objective of the current proposal is to evaluate how the interplay between the timing of neural tissue transplantation after TBI and the state of the cortical microenvironment affects anatomic and functional outcomes. Our central hypothesis is that acute neural tissue transplantation after TBI and removal of the injury perimeter will improve outcomes as a result of enhanced integration of graft neurons with host brain networks and maintenance of host cortex integrity. To test this hypothesis, we will transplant human cortical organoids into rat visual cortex in the chronic or acute setting after a controlled cortical impact injury and assess anatomic and functional outcome measures. In Aim 1, organoids will be transplanted directly into a chronic injury cavity or after resection of the glial scar at the border of the cavity. In Aim 2, organoid grafts will be inserted directly into an acute injury cavity or after the injury margin as been removed. In both of these Aims, organoid health and cell composition as well as host cortex integrity will be assessed histologically. The extent of formation of graft efferents (green fluorescent protein tracing) and afferents (modified rabies virus system for retrograde trans-synaptic tracing) also will be determined. Functional integration of organoid grafts with the host cortex will be investigated using in vivo techniques for recording extracellular neural activity and visual stimulation of the host animal. In Aim 3, we will examine how modulating the activity of organoids using optogenetic stimulation impacts their connectivity and integration with the chronically or acutely injured brain. The proposed research is innovative in its use of human brain organoids as structured neural tissues for cortical repair after TBI and because it explicitly assesses how the timing of transplantation affects outcomes. We expect that the proposed studies will elucidate conditions that result in improved outcomes after organoid transplantation while also identifying the limitations of currently available neural tissue substrates. These expected outcomes will advance the field of cortical repair after TBI by reinvigorating the concept of cell replacement therapy and inspiring novel strategies for modulating graft integration with the brain to achieve specific therapeutic goals.

项目摘要/摘要 脑皮质损伤经常发生在创伤性脑损伤（TBI）的严重程度范围内。不 存在疗法以对抗由这些伤害造成的神经和认知缺陷 负责TBI后实质性残疾。受伤后恢复大脑功能的有前途的策略是 细胞更换。与宿主皮质连接并用作补充皮质的神经组织 处理模块是这种方法特别有趣的候选人。当前可用的组织底物 适用于翻译的，包括从患者匹配的干细胞系中得出的人脑器官， 请勿完全概括皮层的结构或微路。但是，它们仍然可以习惯 研究有关神经组织与宿主大脑整合的杰出问题。一个基本问题 尚未系统地检查这是TBI后细胞更换的最佳时机。总体 当前建议的目的是评估神经组织时间之间的相互作用 TBI和皮质微环境状态后的移植会影响解剖和功能 结果。我们的中心假设是TBI后的急性神经组织移植和损伤去除 由于宿主脑网络的增强了移植神经元的整合，外围将改善结果 并维护主机皮层完整性。为了检验这一假设，我们将移植人类皮质器官 在受控皮质撞击损伤后进入慢性或急性环境中的大鼠视觉皮层并评估解剖学 和功能结果指标。在AIM 1中，类器官将直接移植到慢性损伤腔中 或切除腔边界的神经胶质疤痕。在AIM 2中，将直接插入器官移植物 去除急性损伤腔或损伤边缘后。在这两个目标中，Organoid Health 细胞组成以及宿主皮层完整性将通过组织学评估。形成的程度 移植物传出（绿色荧光蛋白示踪）和传入（改良的狂犬病病毒系统逆行 也将确定反式突触示踪）。器官移植物与宿主皮层的功能整合将 可以使用体内技术记录细胞外神经活动和视觉刺激的研究 宿主动物。在AIM 3中，我们将检查如何使用光遗传学刺激调节器官的活性 影响它们与长期或急性损伤大脑的连通性和整合。拟议的研究是 在TBI和 因为它明确评估移植时间如何影响结果。我们期望提议 研究将阐明细节移植后改善预后的条件 确定当前可用的神经组织底物的局限性。这些预期的结果将 通过重振细胞替代疗法和 激发新的策略，以调节移植物与大脑的整合以实现特定的治疗目标。