Functional contribution of neural stem cells in stroke

中风是老年人死亡和残疾的主要原因。然而，体内中风实验研究，包括神经保护和细胞替代策略的评估，几乎普遍依赖于年轻成年动物的中风模型，因为它们更容易获得，成本更低，健康问题更少。与成熟的年轻人相比，老年人的组织和器官（包括大脑）的基线功能和适应能力明显下降，因此受到中风的损害比年轻人更严重，功能恢复也更差。针对中风动物模型有效的神经保护药物的人体试验持续失败，进一步表明动物模型与人类疾病之间的差异可能具有重要的临床应用价值。因此，更好地了解年龄如何影响中风后对治疗干预的反应，对于合理制定有效的治疗措施至关重要。成人大脑中神经发生的证明，以及中风后大脑缺血区域中具有产生神经元能力的增殖细胞的存在，重新点燃了我们通过内源性神经细胞替代重建受损组织的希望。然而，在临床应用细胞疗法治疗中风之前，需要解决的关键问题包括新生成的细胞在多大程度上成为完全成熟的神经元，并有助于老年大脑中风后的功能恢复。我们假设新生成的神经元是正常脑功能所必需的，也有助于中风后老年大脑的功能恢复。我们还假设，中风后的功能结果可能通过药物工具改善，这些药物工具可以改变年轻人和老年人大脑中NSCs的增殖、迁移或分化，尽管这种影响的程度可能随年龄而变化。在特异性目标1中，我们将研究神经发生在老龄（24月龄）小鼠正常脑功能中的作用。在特异性目标2中，我们将评估诱导性消融神经发生是否会加剧老年小鼠实验性脑卒中的功能结局。在特异性目标3中，我们将确定药物诱导的新生细胞数量的增加是否会改善年轻成年和老年小鼠中风后的功能恢复。拟议实验的长期目标是，通过研究中风诱导的老年大脑神经发生的功能贡献，更好地理解正常衰老和与年龄相关的神经系统疾病（如中风）中控制神经发生的基本原理。

Stroke is a major cause of death and disability in the elderly. However, in vivo experimental stroke studies, including the evaluation of neuroprotective and cell replacement strategies, have relied almost universally on models of stroke in young adult animals due to their easier availability, lower cost and fewer health problems. Compared to mature young adults, the elderly show substantial declines of baseline functions and adaptive capacities in their tissues and organs, including brain, and are thus more severely impaired by stroke than are young adults and have poorer functional recovery. The persistent failure of human trials targeted at neuroprotective agents, which are effective in animal model of stroke, further indicates that the discrepancy between animal models and human diseases could have important clinical application. Therefore, a better understanding of how age affects the response to therapeutic interventions after stroke is crucially important for rational development of effective treatment. The demonstration of neurogenesis in adult brains and of the presence of proliferating cells with the ability to give rise to neurons in the ischemic regions of brains after stroke have reinvigorated our hopes of rebuilding damaged tissues by endogenous neural cell replacement. However, critical issues that need to be addressed before clinical application of cell-based therapies for stroke include the extent to which newly generated cells become fully mature neurons and contribute functional recovery from stroke in the aged brain. We hypothesize that newly generated neurons are required for normal brain function and also contribute functional recovery of aged brains after stroke. We also hypothesize that functional outcome after stroke might be improved by pharmaceutical tools that modify the proliferation, migration or differentiation of NSCs in both young adult and aged brains, although the magnitude of this effect may vary with age. In Specific Aim 1, we will investigate the role of neurogenesis in normal brain functions in aged (24-month-old) mice. In Specific Aim 2, we will evaluate whether the inducible ablation of neurogenesis exacerbates functional outcome from experimental stroke in aged mice. In Specific Aim 3, we will determine whether pharmacologically-induced increases in the number of newborn cells will improve functional recovery from stroke in young adult and aged mice. The long-term goal of the proposed experiments is, by studying the functional contribution of stroke-induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke.