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.

项目摘要/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的炎症性疾病在美国影响近一百万人。年龄是疾病进展的主要驱动力在MS中，具有MS的老年人的转化率更高，转化为继发性MS（SPM），这是一种疾病表型，以随着时间的推移对神经功能的进行性忧虑和对MS疾病改良疗法的抗性。 SPM的发作可以延迟或通过早期预防 MS的积极治疗；但是，该策略涉及使用较高的风险疗法，因此很重要确定那些将从这种治疗策略中获得最大好处的人。当前对衰老的理解 MS大多限于MS患者年代年龄的流行病学研究。越来越多的证据关于衰老的生物学机制，表明通常反映不正确的个体之间的差异按时间顺序排列。这些机制涉及遗传途径和生化过程调节随时间损害的积累，有时会压倒补偿性修复机制并导致与年龄有关的下降。测量MS的生物年龄将通过哪个年龄影响疾病病程并确定有转化为SPM的患者。尽管如此， MS患者之间生物年龄的差异尚未得到充分的特征，以及生物衰老的疾病病程尚不清楚。这项拟议的研究将是第一个测量多重的研究使用已建立的衰老生物标志物在内的生物衰老的独特标志反映端粒损耗，p16ink4a作为细胞感应的标记，表观遗传时钟作为一个与年龄相关的DNA甲基化模式的度量。对于AIM 1，我们将测量近似序列 MS以及年龄和性别匹配的健康对照患者的生物标志物老化的生物标志物。对于AIM 2，我们将确定衰老的生物标志物及其与MS疾病特征的关联之间的关联分段研究和探索性纵向观察一年。这项研究将确定各种衰老机制对MS疾病结局的差异贡献，这代表了至关重要的一步确定可能从早期的高强度疗法中受益的患者患疾病较差的患者防止或延迟SPM的发作。该奖项将支持申请人作为临床科学家的发展通过将Geroscience的原理与神经病学结合起来。目标的成功完成将奠定未来职业发展奖的基础，并带来合并的机会测量生物衰老的测量，以识别RRM的个体较高的转化为SPM的人可能会受益于早期积极治疗。