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Functional recovery from acute brain injury via human neural stem cell transplantation

通过人类神经干细胞移植从急性脑损伤中恢复功能

基本信息

批准号：
9315177
负责人：
JASON P WEICK
金额：
$ 26.54万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9315177
关键词：
Acute Acute Brain Injuries Address Adult Adverse effects Aging American Anatomy Animal Model Animals Baby Booms Behavior Behavioral Brain Cause of Death Cell Transplantation Cell Transplants Cells Cerebral Ischemia Chronic Clinical Clinical Trials Data Dependence Disabled Persons Epidemic Future Generations Goals Health Heart Diseases Human In Vitro Incidence Individual Inflammation Injury Intervention Investigation Ischemia Ischemic Brain Injury Ischemic Stroke Mediating Modeling Motor Neuronal Plasticity Neurons New Mexico Optics Outcome Output Pathway interactions Patients Peripheral Phase I Clinical Trials Physiological Plant Roots Prevention Process Recovery Recovery of Function Recruitment Activity Replacement Therapy Reporting Safety Sensorimotor functions Sensory Societies Stem cells Stroke Survivors Synapses Testing Therapeutic Intervention Time Tissues Transplantation Treatment Efficacy United States Universities angiogenesis base behavioral outcome brain cell brain parenchyma brain tissue cell type cost disability effective therapy experimental study human embryonic stem cell human pluripotent stem cell human stem cells improved in vivo insight ischemic lesion mouse model nerve stem cell nerve supply neurotransmitter release optogenetics paracrine pre-clinical preclinical study progenitor relating to nervous system repaired sensory system simulation stroke recovery stroke survivor stroke therapy vesicular release

项目摘要

SUMMARY Stroke represents a major health issue not only as a cause of death but because most people survive their first stroke, leaving victims permanently disabled. With an aging baby boom generation in the United States, incidence of stroke and costs to society propose to reach epidemic proportions within the next two decades. While prevention efforts have significantly reduced lethality, few effective treatment options exist to provide patients with a means of recovery, and none exist to address the root cause of the problem, loss of brain tissue. Recently however, successful outcomes from cell replacement therapies in pre-clinical studies have led to a number of clinical trials which have demonstrated safety and efficacy for a variety of cell types. Interestingly, many of the mechanisms attributed to transplanted mediated recovery converge on the activity- regulated release of paracrine factors from transplant to host. In the current study, we propose first to validate that transplanted human pluripotent stem cell-derived neurons (hPSNs) improve behavioral recovery in a mouse model of focal ischemia that is amenable to mechanistic and manipulation studies (Specific Aim 1). We will then use this model to test whether optogenetic stimulation of hPSNs can augment behavioral recovery from stroke (Specific Aim 2). Lastly, multiple lines of evidence suggest that functional integration of transplanted cells with host tissue is critical for long-term benefits of cell replacement. In support of this, we have recently demonstrated in uninjured animals that human embryonic stem cell-derived neurons (hPSNs) can functionally integrate with host circuitry after transplantation, and can cause changes to overall excitability in vitro. In the Specific Aim 3 we will test whether and how transplanted hPSNs are functionally integrating with host circuits in vivo to understand how we might augment future intervention strategies. The impact of answering these questions proposes to improve efficacy of cell-based therapeutic interventions.

摘要中风是一个主要的健康问题，不仅是死亡的原因，而且因为大多数人在第一次中风后存活了下来中风，使患者永久残疾。随着美国婴儿潮一代的老龄化，中风的发病率和给社会造成的代价建议在未来20年内达到流行病的比例。虽然预防工作大大降低了致命性，但几乎没有有效的治疗选择来提供患者有康复的手段，却没有解决问题的根本原因，即大脑丧失组织。然而，最近，临床前研究中细胞替代疗法的成功结果导致了一些临床试验已经证明了对各种细胞类型的安全性和有效性。有趣的是，许多归因于移植介导的恢复的机制都集中在活动上- 调节旁分泌因子从移植到宿主的释放。在目前的研究中，我们建议首先验证移植的人多能干细胞衍生神经元(HPSNs)改善了大鼠的行为恢复适合于机制和操作研究的局灶性脑缺血的小鼠模型(特定目标1)。我们然后，我将使用这个模型来测试hPSNs的光遗传刺激是否可以增强行为恢复从中风(特定目标2)开始。最后，多条证据表明，与宿主组织一起移植的细胞对于细胞替换的长期好处至关重要。为了支持这一点，我们最近在未受伤的动物身上证明了人类胚胎干细胞来源的神经元(HPSNs) 移植后可以与宿主电路功能集成，并可能导致整体兴奋性的变化在试管中。在具体目标3中，我们将测试移植的hPSN是否以及如何在功能上与体内的宿主回路，以了解我们可能如何增强未来的干预策略。网络的影响回答这些问题提出了提高基于细胞的治疗干预的有效性。