Immune System Aging in Parkinson’s and Alzheimer’s disease: Epigenetics, biologic aging, and heightened immune states in a population-based study

帕金森病和阿尔茨海默病的免疫系统衰老：基于人群的研究中的表观遗传学、生物衰老和增强的免疫状态

• 批准号: 10396067
• 负责人: Kimberly Paul
• 金额: $ 14.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396067
• 关键词: Adaptive Immune System; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Atrophic; Award; Biological; Biological Aging; Biological Markers; Biology; Blood; Brain; Brain Diseases; Cell Lineage; Cells; Cerebrospinal Fluid; Chronic; Communities; Complex; DNA Methylation; Data; Data Analyses; Data Science; Dementia; Development; Development Plans; Disease; Disease Outcome; Disease Progression; Doctor of Philosophy; Environmental Exposure; Epidemiologist; Epidemiology; Epigenetic Process; Exhibits; Foundations; Funding; Genes; Genomics; Goals; Immune; Immune signaling; Immune system; Immunologic Markers; Impaired cognition; Inflammaging; Inflammation; Knowledge; Lead; Leadership; Learning; Leukocytes; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentors; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methods; Modeling; Modernization; National Institute of Environmental Health Sciences; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurology; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Population Research; Population Sciences; Population Study; Process; Public Health Schools; Research; Research Personnel; Research Priority; Resource Development; Resources; Risk; Risk Factors; Role; Science; Serum; Statistical Methods; Symptoms; Systems Biology; Technology; Time; Training; Training Support; Variant; Work; adaptive immune response; age related; base; biological systems; brain morphology; career; career development; cohort; cytokine; design; epidemiologic data; epidemiology study; epigenetic marker; fluorodeoxyglucose positron emission tomography; genetic architecture; genome wide association study; immune activation; immune system function; immunosenescence; innovation; insight; medical schools; metabolic profile; metabolome; metabolomics; methylation biomarker; neurodegenerative phenotype; professor; response; skills; small molecule; tau Proteins; tool

PROJECT ABSTRACT. Kimberly Paul, PhD, MPH, is a neurologic and aging disease epidemiologist whose research career goals focus around using modern, “omic” technologies to define the neurodegenerative disease process and elucidate risk at a biologic level, integrating a systems biology approach, in population-based studies. The research she proposes, entitled “Immune System Aging in Parkinson’s and Alzheimer’s disease-related dementia: Epigenetics, biologic aging, and heightened immune states”, combines advanced statistical methods and a systems biology modeling approach with high-throughput omics markers to study immune system aging in neurodegenerative disease patients relative to community-based controls; followed by relating epigenetic markers of inflamm-aging to symptom development and multiple metabolomics measurements over time. Candidate & Mentoring Team: Dr. Paul is a Postdoctoral Scholar in the Department of Epidemiology at the Fielding School of Public Health (UCLA) and will transition to an Assistant Professor in the Department of Neurology, David Geffen School of Medicine. Dr. Paul was previously awarded an NIEHS F32 to investigate how metabolic dysfunction mediates the association between ambient environmental exposures and primarily Alzheimer’s disease-related dementia (ADRD). For this work, she was awarded the prestigious Chancellor’s Award for Postdoctoral Research at UCLA. Her research priorities have developed into bringing biology and mechanism into population and data science. The proposed career development plan will build upon her previous training with goals to enhance her trajectory toward becoming an independent investigator, including experiential and didactic learning in design, methods and data interpretation, while developing the leadership and professional skills required to lead an independent research lab and execute an R01. Dr. Paul has assembled a strong mentoring team with renowned expertise, commitment, and available resources to support her training. Research Summary: The research aims of this K01 proposal focus on using a systems biology pipeline to investigate immune system aging in Parkinson’s disease (PD) and ADRD patients, using blood-based epigenetics to define immune states. The purpose of this proposal is to investigate how these immune markers and measures of accelerated immune system aging relate to onset, symptom development, and trajectories of metabolomic changes using two population-based studies. The hypothesis being that immune profiles which reflect “inflamm-aging” (chronic, low-level inflammation states) and immunosenescence will be related to faster symptom development. Furthermore, longitudinal metabolomics and targeted gene sequencing will give insight into endogenous risk and the systemic response related to different immune states as symptoms develop. This award will provide Dr. Paul the research opportunity and career development resources to continue to excel and establish herself as an independent investigator and leader in her field, conducting innovative research, combining systems biology, omic technologies, and population-based research.

项目摘要。 Kimberly Paul，博士，公共卫生硕士，是一位神经病学和衰老疾病流行病学家，其研究职业目标集中在 围绕使用现代“组学”技术来定义神经退行性疾病过程并阐明风险 在生物学层面，将系统生物学方法整合到基于人群的研究中。 题为“帕金森病和阿尔茨海默病相关痴呆症中的免疫系统老化： “表观遗传学、生物衰老和消化免疫状态”，结合了先进的统计方法和 一种具有高通量组学标记的系统生物学建模方法，用于研究免疫系统衰老 神经退行性疾病患者与基于社区的对照相关；其次是相关表观遗传； 随着时间的推移，炎症老化到症状发展和多种代谢组学测量的标志物。 候选人及指导团队：Paul 博士是该大学流行病学系的博士后学者 菲尔丁公共卫生学院（加州大学洛杉矶分校）并将转任该系助理教授 大卫·格芬医学院神经学教授 Paul 博士之前曾获得 NIEHS F32 来研究如何进行研究。 代谢功能障碍介导周围环境暴露与主要 由于这项研究，她因阿尔茨海默病相关痴呆症 (ADRD) 获得了著名的校长奖。 加州大学洛杉矶分校博士后研究奖她的研究重点已发展为将生物学和 拟议的职业发展计划将建立在她之前的基础上。 旨在增强她成为一名独立调查员的目标的培训，包括体验式培训 以及设计、方法和数据解释方面的教学学习，同时培养领导力和 Paul 博士组建了一个领导独立研究实验室并执行 R01 所需的专业技能。 强大的指导团队拥有著名的专业知识、承诺和可用资源来支持她的培训。 研究摘要：本 K01 提案的研究目标侧重于使用系统生物学流程 使用基于血液的方法研究帕金森病 (PD) 和 ADRD 患者的免疫系统老化情况 该提案的目的是研究这些免疫标记物如何通过表观遗传学来定义免疫状态。 加速免疫系统老化的措施与发病、症状发展和轨迹有关 使用两项基于人群的研究得出的代谢组学变化的假设是免疫特征。 反映“炎症老化”（慢性、低水平炎症状态），免疫衰老将与更快 此外，纵向代谢组学和靶向基因测序将提供洞察力。 随着症状的发展，内源性风险和与不同免疫状态相关的系统反应。 该奖项将为 Paul 博士提供继续取得卓越成就的研究机会和职业发展资源 并确立自己作为所在领域的独立研究者和领导者的地位，开展创新研究， 结合系统生物学、组学技术和基于人群的研究。