Molecular correlates of sub-regional thalamic degeneration in multiple sclerosis

多发性硬化症亚区域丘脑变性的分子相关性

• 批准号: 10553206
• 负责人: Ranjan Dutta
• 金额: $ 20.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553206
• 关键词: Acute; Address; Affect; Anatomy; Atrophic; Attention; Autopsy; Axon; Biological Assay; Brain; Brain region; Cell Nucleus; Cells; Central Nervous System; Clinical; Clinical/Radiologic; Cognitive; Collection; Data; Demyelinating Diseases; Demyelinations; Disease; Fatigue; Foundations; Future; Genes; Goals; Immune; Impaired cognition; Impairment; Individual; Inflammatory; Knowledge; Lateral Geniculate Body; Lesion; Magnetic Resonance Imaging; Measures; Mediating; Molecular; Molecular Profiling; Monitor; Motor; Multiple Sclerosis; Mutation; Nerve Degeneration; Nervous System Physiology; Neuroglia; Neurologic; Neurons; Nuclear; Pathology; Patients; Pattern; Population; Pulvinar structure; Radiology Specialty; Reporting; Research; Research Personnel; Resolution; Sampling; Secondary to; Sensory; Small Nuclear RNA; Structure; Syndrome; Thalamic structure; Validation; brain magnetic resonance imaging; central nervous system demyelinating disorder; chronic demyelination; cohort; comparative; design; disability; genetic signature; gray matter; human disease; information processing; multiple sclerosis patient; neuron loss; novel; prevent; single nucleus RNA-sequencing; single-cell RNA sequencing; therapy development; transcriptomics; white matter

ABSTRACT Multiple sclerosis (MS) is an immune-mediated disease of the human central nervous system (CNS) that involves demyelination and degeneration of both white matter and gray matter. Deep grey-matter structures such as the thalamus have received significant attention in MS research due to their early volume loss. The thalamus is far more than just a “relay station”; organizing afferent and efferent information processing, its connectivity to multiple regions implicates it in fatigue as well as motor, cognitive, and sensory impairments in individuals with MS. Thalamic atrophy is a predictor of disability and cognitive impairment in all disease courses of MS, as well as a predictor for conversion of clinically- isolated syndrome into MS. While thalamic atrophy is established in MS, the exact mechanisms underlying thalamic degeneration are not well-characterized. We have assembled a strong team of investigators with interdisciplinary and complementary expertise in order to identify the molecular correlates of the thalamic degeneration in MS. Recent data support the hypothesis that demyelination outside the thalamus, affecting the functional and anatomic connections, may drive selective neurodegeneration within the thalamus. Preliminary results have identified three thalamic regions: lateral geniculate nucleus (LGN), pulvinar (PV) nucleus, and centro-medial (CM) nucleus as a) having preferential volume loss, and b) significantly correlating with greater neurological disability in patients with progressive MS. We therefore hypothesize that preferential volume loss of certain thalamic sub- regions may be due selective vulnerability of their neuronal/glial populations. Using postmortem MRI, we identified cohorts of postmortem MS brains with mild or severe volume loss and minimal demyelination in the thalamus. In addition, we also include a recently-identified novel group of MS patients (termed myelocortical MS) without any white-matter lesions, but comparable thalamic atrophy. The main goal of this exploratory proposal is therefore to generate, identify, and validate a molecular pattern representative of thalamic volume loss in MS using single-cell RNA sequencing (sc-RNA seq). The proposed study will use well-characterized samples for Aim 1a) sc-RNA seq; Aim 1b) spatial transcriptomic assays; and Aim 1c) validation of novel cell clusters to investigate the molecular alterations underlying thalamic atrophy in MS. These studies will reveal the genetic signatures associated with thalamic regions that are vulnerable and contribute to volume loss in MS patients. Successful completion of the current study will provide a significant step forward towards future research in monitoring and eventually preventing thalamic atrophy and neurodegeneration in MS patients.

抽象的 多发性硬化症（MS）是人类中枢神经系统（CNS）的免疫介导的疾病 这涉及白质和灰质的脱髓鞘和变性。深灰色 丘脑等结构在MS研究中受到了极大的关注 音量损失。丘脑不仅仅是一个“继电器站”。组织传入和高效 信息处理，其与多个区域的连通性在疲劳和电机中实现了它， MS患者的认知和感觉障碍。丘脑萎缩是残疾的预测指标 以及MS的所有疾病课程中的认知障碍，以及临床上转化的预测指标 分离的综合征到MS。虽然在MS中建立丘脑萎缩，但确切的机制 丘脑的潜在变性没有很好地表征。我们组建了一个强大的团队 具有跨学科和完整专业知识的研究人员，以确定分子 MS中丘脑变性的相关性。最近的数据支持脱髓鞘的假设 在丘脑外影响功能和解剖连接的外部，可能会推动选择性 丘脑内的神经变性。初步结果已经确定了三个丘脑区域：稍后 基因核（LGN），pulvinar（PV）核和Centro-Media（CM）核作为A）具有 优先体积损失，b）与患者的神经残疾更大相关 与渐进式MS。因此，我们假设某些丘脑亚属性的首选体积损失 区域可能是适当的神经/神经胶质种群的选择性脆弱性。使用后MRI， 我们鉴定了尸体MS大脑的队列，其体积轻度或重度损失和最小 丘脑中的脱髓鞘。此外，我们还包括最近确定的MS小组 患者（称为肌层MS）没有任何白色可能性病变，但可比的丘脑萎缩。 因此，该探索性建议的主要目标是生成，识别和验证分子 使用单细胞RNA测序（SC-RNA SEQ）代表MS中丘脑体积损失的模式。 拟议的研究将使用特征良好的样品作为AIM 1A）SC-RNA SEQ；目标1B）空间 转录组测定；目标1C）验证新细胞簇以研究分子 MS中丘脑萎缩的基础改变。这些研究将揭示遗传特征 与脆弱的丘脑区域相关，并导致MS患者的体积损失。 当前研究的成功完成将为未来的研究提供重要的一步 MS患者的监测，有时预防丘脑萎缩和神经退行性。