Immune Regulation of Neural Stem Cell Program in EAE

描述（由申请人提供）：成年哺乳动物中枢神经系统含有一群未成熟、未分化、多能细胞，即神经干细胞（NSC），可用于神经退行性和脱髓鞘疾病的修复。神经干细胞又可以产生少突胶质细胞祖细胞（OPC）和其他髓鞘形成细胞，以及神经和神经胶质前体。神经干细胞修复成人损伤的能力已在几个实验系统中得到证实。然而，在多发性硬化症及其动物模型中，实验性自身免疫性脑脊髓炎（EAE）的髓鞘再生和神经再生并没有达到足够的程度。在上一个资助期间，我们已经研究了炎症对体内和体外神经干/祖细胞多能性的影响。我们发现，神经干细胞增殖，开始分化，并迁移出脑室下区在急性期的疾病。但随着疾病的进展，干细胞的增殖会减弱。此外，我们观察到，在慢性EAE期间，小胶质细胞在没有炎症浸润的情况下保持激活。这种情况让人想起多发性硬化症的慢性期，其中在MRI上没有钆增强病变的情况下发生神经变性和脑实质丧失。我们将研究的假设，慢性激活的小胶质细胞负责，至少在干细胞功能障碍的一部分。我们将在以下目标中讨论这一假设。目标1.急性和慢性激活的小胶质细胞与神经祖细胞的差异相互作用。目标2.神经干细胞如何调节SVZ中的小胶质细胞活化。目标3。我们将研究慢性小胶质细胞激活的逆转是否会恢复正常的NSC功能。这些研究将对我们理解多发性硬化症神经退行性变的发病机制产生影响，并提供一个可用于慢性疾病靶向治疗的模型。

DESCRIPTION (provided by applicant): The adult mammalian central nervous system contains a population of immature, undifferentiated, multipotent cells, neural stem cells (NSCs) that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may, in turn, give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells, as well as neural and glial precursors. The capacity of NSCs to repair damage in the adult has been demonstrated in several experimental systems. However, in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) remyelination and neuro-regeneration do not occur to a sufficient extent. During the previous funding period we have examined the effects of inflammation on the multipotentiality of neural stem/progenitor cells in vivo and in vitro. We found that NSCs proliferate, start to differentiate, and migrate out of the subventricular zone during the acute phase of the disease. But as the disease progresses proliferation of the stem cells subsides. Furthermore, we have observed that during chronic EAE, microglia remain activated in the absence of inflammatory infiltrates. This situation is reminiscent of the chronic phase of multiple sclerosis, where neuro-degeneration and loss of brain parenchyma occur in the absence of gadolinium enhancing lesions on MRI. We will examine the hypothesis that chronically activated microglia are responsible, at least in part for the dysfunction in stem cell function. We will address this hypothesis in the following aims. Aim 1. Differential interaction of acutely versus chronically activated microglia with neural progenitor cells. Aim 2. How do NSCs modulate microglial activation in the SVZ. Aim 3. We will examine if reversal of chronic microglia activation will restore normal NSC functionality. These investigations will have an impact on our understanding of the pathogenesis of neuro-degeneration in multiple sclerosis and provide a model that may be used to target treatments for chronic disease.