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: 10554384
• 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/10554384
• 关键词: Acceleration; 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; Central Nervous System; 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; Gene set enrichment analysis; Genes; Genomics; Goals; Immune; Immune signaling; Immune system; Immunologic Markers; Impaired cognition; Inflammaging; Inflammation; Innate Immune Response; Innate Immune System; Knowledge acquisition; Lead; Leadership; Learning; Leukocytes; Link; Measurement; Measures; Mediating; Mentors; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methods; Modeling; Modernization; National Institute of Environmental Health Sciences; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurology; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Population Research; Population Sciences; Population Study; Postdoctoral Fellow; Process; Proliferating; Public Health Schools; Research; Research Personnel; Research Priority; Resource Development; Resources; Risk; Risk Factors; Role; Science; Serum; Statistical Methods; Symptoms; System; Systems Biology; Technology; Time; Training; Training Support; Variant; Work; adaptive immune response; age related; 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。 金伯利·保罗，博士，公共卫生硕士，神经学和老年病流行病学家，他的研究生涯目标集中在 围绕使用现代的“基因组”技术来定义神经退行性疾病的过程和阐明风险 在生物学层面，将系统生物学方法整合到基于种群的研究中。她的研究 提出题为“帕金森氏症和阿尔茨海默病相关痴呆的免疫系统老化： 表观遗传学、生物老化和免疫状态增强“，结合了先进的统计方法和 应用高通量组学标记研究免疫系统衰老的系统生物学建模方法 与社区对照相关的神经退行性疾病患者；其次是相关的表观遗传学 随着时间的推移，炎症老化的标记物对症状发展和多代谢组学的测量。 候选人和指导团队：保罗博士是华盛顿大学流行病学系的博士后学者 菲尔丁公共卫生学院(UCLA)，并将过渡到助理教授在 神经病学，大卫·格芬医学院。保罗博士此前曾被授予NIEHS F32，以研究 代谢功能障碍调节环境暴露与主要疾病的关系 阿尔茨海默病相关痴呆(ADRD)。由于这项工作，她被授予著名的总理 加州大学洛杉矶分校博士后研究奖。她的研究重点已经发展到将生物学和 机制融入了人口和数据科学。拟议的职业发展计划将建立在她之前的基础上 有目标的培训，以增强她成为独立调查员的轨迹，包括经验 在设计、方法和数据解释方面的指导性学习，同时发展领导力和 领导独立研究实验室并执行R01所需的专业技能。保罗博士已经组装了一个 强大的指导团队，具有知名的专业知识、承诺和可用的资源来支持她的培训。 研究综述：本K01提案的研究目标集中在使用系统生物学管道来 以血液为基础研究帕金森病(PD)和ADRD患者的免疫系统老化 表观遗传学来定义免疫状态。这项提议的目的是调查这些免疫标志物是如何 而加速免疫系统老化的衡量标准与发病、症状发展和运动轨迹有关 使用两项基于群体的研究来研究代谢变化。假设是免疫特征是 反映“炎症老化”(慢性、低水平的炎症状态)和免疫衰老会更快相关 症状发展。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，转化为内源性风险和与不同免疫状态相关的系统反应。 该奖项将为保罗博士提供继续出类拔萃的研究机会和职业发展资源。 并确立自己作为独立调查者和所在领域的领导者的地位，进行创新研究， 结合系统生物学、基因组技术和基于种群的研究。