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: 10449474
• 负责人: Ranjan Dutta
• 金额: $ 24.15万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449474
• 关键词: Acute; Address; Affect; Anatomy; Atrophic; Attention; Autopsy; Axon; Biological Assay; Brain; Brain region; Cell Nucleus; Cells; 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; Medial; Mediating; Molecular; Molecular Profiling; Monitor; Motor; Multiple Sclerosis; Mutation; Nerve Degeneration; Nervous System Physiology; Neuraxis; 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; regional atrophy; single-cell RNA sequencing; therapy development; transcriptome sequencing; 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.

摘要