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

该提案将在MS临床前模型中使用细胞特异性和区域特异性转录组学方法 揭示MS中定制的、残疾特异性的神经保护治疗方法的新候选靶点。 行走、视觉和认知的神经通路不同，神经系统内的细胞和分子也不同。 神经解剖区域为它们服务。MS患者的残疾是异质性的， 受影响最严重。因此，我们假设，一个尺寸适合所有神经保护治疗的所有 MS中的残疾可能不可能。相反，需要一种针对残疾人的发现方法。目标1。 在EAE中使用区域特异性星形胶质细胞转录组识别神经退行性机制 重点是脊髓以外的视神经和海马体。目标2。识别神经退行性疾病 EAE中使用区域特异性神经元转录组的机制。目标3。使用特定区域 少突胶质细胞转录组学，以确定在两个互补的髓鞘再生的分子机制， MS模型。目标4。为了开始将发现转化为MS，我们将确定基因的改变是否 MS模型中关键途径的表达发生在使用人尸检组织的MS中。总之，这一提议 将揭示不同的细胞特异性和区域特异性机制，这些机制是行走、视觉和认知的基础。 MS中的残疾

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.