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) 是一种免疫介导的人类中枢神经系统 (CNS) 疾病 这涉及白质和灰质的脱髓鞘和退化。深部灰质 丘脑等结构由于其早期特征而在多发性硬化症研究中受到了极大的关注。 体积损失。丘脑不仅仅是一个“中继站”；组织传入和传出 信息处理，它与多个区域的连接涉及疲劳和运动， 多发性硬化症患者的认知和感觉障碍。丘脑萎缩是残疾的预测因素 多发性硬化症所有病程中的认知障碍和认知障碍，以及临床症状转化的预测因子 孤立综合征转变为多发性硬化症。虽然丘脑萎缩在多发性硬化症中已确定，但确切的机制 潜在的丘脑变性尚不明确。我们组建了一支强大的团队 具有跨学科和互补专业知识的研究人员，以确定分子 MS 丘脑变性的相关性。最近的数据支持脱髓鞘的假设 丘脑外部，影响功能和解剖连接，可能会驱动选择性 丘脑内的神经变性。初步结果确定了三个丘脑区域：外侧丘脑区域 膝状核 (LGN)、枕核 (PV) 和中央内侧 (CM) 核 a) 具有 优先容量损失，b) 与患者更大的神经功能障碍显着相关 患有进行性多发性硬化症。因此，我们假设某些丘脑亚区的优先体积损失 区域可能是由于其神经元/神经胶质细胞群的选择性脆弱性。使用死后核磁共振成像， 我们发现死后多发性硬化症大脑的队列有轻度或严重的体积损失和最小的体积损失。 丘脑脱髓鞘。此外，我们还包括最近发现的一组新的 MS 患者（称为骨髓皮质多发性硬化症）没有任何白质病变，但有类似的丘脑萎缩。 因此，该探索性提案的主要目标是生成、识别和验证分子 使用单细胞 RNA 测序 (sc-RNA seq) 表示 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本来实现目标 1a) sc-RNA seq；目标 1b) 空间 转录组分析；和目标 1c) 验证新型细胞簇以研究分子 MS 中丘脑萎缩的改变。这些研究将揭示遗传特征 与脆弱的丘脑区域有关，并导致多发性硬化症患者的体积损失。 当前研究的成功完成将为未来的研究迈出重要一步 监测并最终预防多发性硬化症患者的丘脑萎缩和神经变性。