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

MS 中的神经保护：细胞特异性和区域特异性转录组学方法

• 批准号: 9792301
• 负责人: RHONDA R VOSKUHL
• 金额: $ 44.46万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792301
• 关键词: Address; Adult; Affect; Astrocytes; Autopsy; Cells; Cognition; Disease; Experimental Autoimmune Encephalomyelitis; Gene Expression; Hippocampus (Brain); Human; Modeling; Molecular; Multiple Sclerosis; Nerve Degeneration; Neurologic; Neurons; Oligodendroglia; Optic Nerve; Pathway interactions; Patients; Pre-Clinical Model; Public Health; Spinal Cord; Tissues; Translating; Vision; Vision Disorders; Walking; cognitive disability; disability; improved; middle age; multiple sclerosis patient; neuroprotection; novel; remyelination; transcriptome; transcriptomics

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.

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 揭示针对多发性硬化症量身定制、针对残疾的神经保护治疗方法的新候选目标。 行走、视觉和认知的神经通路不同，大脑中的细胞和分子也不同。 为它们服务的神经解剖区域。 MS 患者的残疾程度各不相同 受影响最严重。因此，我们假设一种方法适用于所有神经保护治疗 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 中的区域特异性星形胶质细胞转录组识别神经退行性机制，此处 重点超越脊髓，聚焦于视神经和海马体。目标#2。识别神经退行性疾病 在 EAE 中使用区域特异性神经元转录组的机制。目标#3。使用特定区域 少突胶质细胞转录组学确定两种互补的髓鞘再生的分子机制 MS 型号。目标#4。为了开始将研究结果转化为 MS，我们将确定基因的改变是否 MS 模型中关键通路的表达发生在使用人体尸检组织的 MS 中。共同提出这个建议 将揭示行走、视觉和认知的不同细胞特异性和区域特异性机制 多发性硬化症的残疾。