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: 10428639
• 负责人: HAN-CHIAO ISAAC CHEN
• 金额: $ 41.11万
• 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/10428639
• 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 大脑皮层损伤在创伤性脑损伤(TBI)的不同严重程度中经常发生。不是 存在治疗方法来对抗由这些损伤引起的神经和认知缺陷，这些损伤是 对颅脑损伤后的实质性残疾负责。损伤后恢复大脑功能的一个有希望的策略是 更换细胞。局部与宿主皮质相连并起辅助皮质作用的神经组织 对于这种方法，处理模块尤其令人感兴趣。目前可用的组织基质 适合翻译的，包括从患者匹配的干细胞系中提取的人脑有机化合物， 不要完全概括大脑皮层的结构或微回路。然而，它们仍然可以用来 调查有关神经组织与宿主大脑整合的突出问题。一个基本问题 尚未系统研究的是颅脑损伤后细胞更换的最佳时机。整体而言 目前的建议的目的是评估神经组织的计时之间的相互作用 颅脑损伤后移植与皮质微环境状态对解剖和功能的影响 结果。我们的中心假设是颅脑损伤后的急性神经组织移植和损伤切除 PERIMETER将改善移植神经元与宿主脑网络整合的结果 以及维持寄主皮层的完整性。为了验证这一假设，我们将移植人类大脑皮层器官。 在受控皮质撞击伤后的慢性或急性环境中进入大鼠的视皮层并评估解剖学 和功能结果衡量标准。在目标1中，有机化合物将被直接移植到慢性损伤的牙洞中。 或在切除空洞边缘的神经胶质瘢痕后。在目标2中，器官移植物将直接植入 进入急性损伤腔内或在损伤边缘被移除后。在这两个目标中，有机物质健康 细胞组成以及宿主皮质的完整性将进行组织学评估。形成的程度 移植物传出(绿色荧光蛋白示踪)和传入(改进的逆行狂犬病病毒系统 跨突触追踪)也将被确定。器官移植物与宿主皮质的功能整合将 使用活体技术记录细胞外神经活动和视觉刺激 宿主动物。在目标3中，我们将研究如何利用光遗传刺激来调节有机物的活性。 影响他们与慢性或急性损伤的大脑的连接和整合。拟议的研究是 创新地使用人脑器官作为结构性神经组织用于脑外伤后皮质修复和 因为它明确地评估了移植的时机如何影响结果。我们预期拟议的 研究将阐明导致器官移植后结果改善的条件，同时还 确定目前可用的神经组织底物的局限性。这些预期结果将 通过重振细胞替代疗法的概念促进脑外伤后皮质修复领域的发展 启发调节移植物与大脑整合的新策略，以实现特定的治疗目标。