Neuroprotection in MS: A Cell-Specific and Region-Specific Transcriptomics Approach

这项建议将在多发性硬化症临床前模型中使用特定细胞和特定区域的转录组方法 揭示一种量身定制的、针对残疾的、神经保护治疗方法的新候选靶点。 作为行走、视觉和认知基础的神经通路不同，大脑中的细胞和分子也不同 为它们服务的神经解剖区域。多发性硬化症患者的残疾程度是不同的 受影响最严重的。因此，我们假设一种尺寸适用于所有人的神经保护治疗。 多发性硬化症的残疾可能是不可能的。相反，需要一种针对残疾的发现方法。目标1. 使用EAE中特定区域的星形胶质细胞转录组确定神经退行性变机制，此处 聚焦于脊髓以外，视神经和海马体。目标2.确定神经退行性变 在EAE中使用区域特异性神经元转录组的机制。目标#3.使用特定地区 用少突胶质细胞转录物研究两种互补的髓鞘再分化的分子机制 MS模特。目标4：为了开始将研究结果转化为多发性硬化症，我们将确定基因的变化是否 多发性硬化症模型中关键通路的表达发生在多发性硬化症的人体尸检组织中。总而言之，这项提案 将揭示行走、视觉和认知的独特细胞和区域特定机制 多伦多大学的残疾。

This proposal will use a cell-specific and region-specific transcriptomics approach in the MS preclinical model to reveal new candidate targets for a tailored, disability-specific, neuroprotective treatment approach in MS. Neurological pathways underling walking, vision, and cognition differ, as do the cells and molecules within the neuroanatomic regions that serve them. MS patients are heterogeneous with regard to which disability is the most severely affected. Thus, we hypothesize that a one size fits all neuroprotective treatment for all disabilities in MS may not be possible. Rather, a disability specific discovery approach is needed. Aim #1. Identify neurodegenerative mechanisms using the region-specific astrocyte transcriptome in EAE, here focusing beyond spinal cord, on optic nerve and hippocampus. Aim #2. Identify neurodegenerative mechanisms using the region-specific neuronal transcriptome in EAE. Aim #3. Use region-specific oligodendrocyte transcriptomics to determine molecular mechanisms of remyelination in two complementary MS models. Aim #4. To begin to translate findings to MS, we will determine whether the alteration in gene expression in key pathways in MS models occurs in MS using human autopsy tissues. Together, this proposal will reveal distinct cell-specific and region-specific mechanisms underlying walking, vision, and cognitive disability in MS.