Markers of Biological Aging in Multiple Sclerosis

多发性硬化症的生物衰老标志

基本信息

批准号：
10689771
负责人：
Yinan Zhang
金额：
$ 15.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689771
关键词：
Acceleration Activities of Daily Living Affect Age Aging Algorithms Animal Model Award Axon Biochemical Process Biological Biological Aging Biological Markers Biology of Aging CDKN2A gene Cell Aging Cell physiology Cells Central Nervous System Diseases Characteristics Chronic Chronology Clinical Clinical Research Clinical/Radiologic Cognition Cognitive Cross-Sectional Studies Custom DNA Methylation Data Development Disease Disease Outcome Disease Progression Disease remission Enhancing Lesion Epigenetic Process Exhibits Failure Foundations Future Genetic Geroscience Human Immune Immunosuppressive Agents Individual Inflammation Inflammatory K-Series Research Career Programs Language Length Lesion Leukocytes Life Literature Magnetic Resonance Imaging Measurement Measures Mediating Memory Methylation Multiple Sclerosis Myeloid Cells Nervous System Physiology Neurology Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Phase Phenotype Polymerase Chain Reaction Prevalence Progressive Disease Relapse Research Resistance Risk Risk Factors Safety Scientist Secondary Progressive Multiple Sclerosis Secondary to Serum Severity of illness T-Lymphocyte Testing Time Tissues Treatment Efficacy United States Variant age related aggressive therapy brain volume career development disability disease phenotype disease prognosis epidemiology study executive function exhaustion experience high risk improved innovation methylation biomarker methylation pattern molecular marker multiple sclerosis patient multiple sclerosis treatment nano-string neuron loss peripheral blood prevent processing speed remyelination repaired sex telomere treatment strategy verbal visual memory

项目摘要

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the central nervous system affecting nearly one million people in the United States. Age is the predominant driver of disease progression in MS, and older individuals with MS are at higher risk of conversion to secondary-progressive MS (SPMS), which is a disease phenotype marked by progressive worsening of neurological function over time and resistance to MS disease-modifying therapies. The onset of SPMS can be delayed or prevented through early aggressive treatment of MS; nevertheless, this strategy involves using higher risk therapies, so it is important to identify those who will derive the most benefit from this treatment strategy. Current understanding of aging in MS is mostly limited to epidemiological studies of chronological age in patients with MS. Increasing evidence on the biological mechanisms of aging shows variations among individuals that are often inaccurately reflected by their chronological age. These mechanisms involve genetic pathways and biochemical processes that regulate the accumulation of damage over time, which eventually overwhelm compensatory repair mechanisms and lead to age-related decline. Measuring biological age in MS would uncover mechanisms by which age affects disease course and identify patients at risk of conversion to SPMS. Nevertheless, differences in biological age among people with MS have not been adequately characterized, and the effects of biological aging on disease course remain unknown. This proposed study will be the first to measure multiple distinct hallmarks of biological aging using established aging biomarkers including leukocyte telomere length reflecting telomere attrition, p16INK4a as a marker of cellular senescence, and the epigenetic clock as a measure of age-associated DNA methylation patterns. For aim 1, we will measure the aforementioned serum aging biomarkers in patients with MS and age- and sex-matched healthy controls. For aim 2, we will determine associations between biomarkers of aging and their associations with MS disease characteristics in a cross- sectional study and with exploratory longitudinal observations for one year. This research will determine the differential contributions of various aging mechanism to MS disease outcomes and represents a critical step to identifying patients at risk of worse disease outcomes who may benefit from early high-intensity therapies to prevent or delay the onset of SPMS. This award will support the applicant’s development as a clinician scientist by integrating principles of geroscience with neurology. The successful completion of the aims will lay the foundation for a future career development award application and lead to opportunities for incorporating measurements of biological aging to identify individuals with RRMS at higher risk for conversion to SPMS who may benefit from early aggressive treatment.

项目概要/摘要多发性硬化症 (MS) 是一种慢性免疫介导的中枢神经系统炎症性疾病影响美国近一百万人。年龄是疾病进展的主要驱动因素。患有多发性硬化症的患者，患有多发性硬化症的老年患者转化为继发性进行性多发性硬化症 (SPMS) 的风险较高，这是一种以神经功能随时间逐渐恶化为特征的疾病表型对 MS 疾病缓解疗法的耐药性 SPMS 的发作可以通过早期延迟或预防。积极治疗多发性硬化症；然而，这种策略涉及使用风险较高的疗法，因此很重要以确定哪些人将从这种治疗策略中获得最大的益处。 MS 大多局限于 MS 患者实际年龄的流行病学研究。关于衰老的生物学机制的研究表明，个体之间存在差异，而这些差异往往无法准确反映这些机制涉及遗传途径和生化过程。随着时间的推移调节损伤的积累，最终压倒补偿性修复测量多发性硬化症的生物年龄将揭示机制。年龄会影响疾病进程并识别有转为 SPMS 风险的患者。多发性硬化症患者的生物学年龄差异尚未得到充分表征，并且多发性硬化症患者的影响生物衰老对疾病进程的影响仍然未知，这项拟议的研究将是第一个测量多种疾病的研究。使用已建立的衰老生物标志物（包括白细胞端粒长度）来确定生物衰老的独特特征反映端粒磨损，p16INK4a 作为细胞衰老的标记，表观遗传时钟作为测量与年龄相关的 DNA 甲基化模式对于目标 1，我们将测量上述血清。对于目标 2，我们将确定 MS 患者以及年龄和性别匹配的健康对照的衰老生物标志物。衰老生物标志物之间的关联及其与多发性硬化症疾病特征的关联这项研究将通过为期一年的截面研究和探索性纵向观察来确定。各种衰老机制对多发性硬化症疾病结果的不同贡献，是迈出关键一步处于疾病结果更差风险的患者可能会受益于早期高强度治疗预防或延迟 SPMS 的发生该奖项将支持申请人作为临床科学家的发展。通过将老年科学原理与神经学相结合，目标的成功实现将奠定基础。为未来职业发展奖申请奠定基础，并带来合并的机会测量生物衰老，以识别患有 RRMS 且转换为 SPMS 风险较高的个体可能会受益于早期积极治疗。