Identification and characterization of molecular subtypes of Alzheimer's disease associated with cognitive function through cross-omics data integration

通过跨组学数据整合识别和表征与认知功能相关的阿尔茨海默病分子亚型

• 批准号: 10722083
• 负责人: Abdallah M Eteleeb
• 金额: $ 14.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722083
• 关键词: Address; Advisory Committees; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Animal Model; Autopsy; Award; Biological; Biological Markers; Biology; Blood; Brain; Brain region; Cerebrospinal Fluid; Chromatin Remodeling Factor; Clinical; Clinical Trials; Cognitive; DNA Methylation; Data; Data Set; Dedications; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Educational workshop; Encapsulated; Environment; Epigenetic Process; Feedback; Foundations; Funding; Future; Genes; Genetic; Genomics; Goals; Heterogeneity; Human; Impaired cognition; Individual; Journals; K-Series Research Career Programs; Knowledge; Leadership; Learning; Machine Learning; Malignant Neoplasms; Medical Research; Mentors; Mentorship; Modality; Modeling; Molecular; Molecular Profiling; Multiomic Data; Nerve Degeneration; Neurodegenerative Disorders; Neurology; Neurosciences; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Proteomics; Regulation; Reporting; Research; Risk; Techniques; Testing; Training; Training Programs; United States; Universities; Untranslated RNA; Validation; Washington; Work; biological systems; biomarker identification; blood-based biomarker; cerebral atrophy; clinically relevant; cognitive function; cohort; data integration; design; digital; disorder subtype; effective therapy; experience; genetic risk factor; histone modification; human old age (65+); illness length; improved; innovation; insight; medical schools; model organism; molecular marker; molecular subtypes; mouse model; multiple datasets; neuropathology; novel; novel therapeutics; patient subsets; potential biomarker; precision medicine; sex; skills; spatiotemporal; specific biomarkers; symposium; tau Proteins; trait; transcriptomics

Project Summary/Abstract The goal of this mentored career development award is to provide a robust course of training in the biology of neurodegeneration and aging for Dr. Eteleeb, Ph.D., a candidate with extensive experience in genomics, omics, and machine learning, to enable his transition to research independence. Washington University School of Medicine is a nationally recognized leader in medical research and provides an outstanding environment for the candidate’s training with world-renowned figures in the fields of Alzheimer’s disease (AD) and aging. This proposal will be conducted under the mentorship of an excellent interdisciplinary team of leaders with extensive and complementary sets of expertise in AD, aging, neuroscience, genetics, and cross-omics who are dedicated to support Dr. Eteleeb in completing his research and training goals proposed in this award. With the guidance of this team, Dr. Eteleeb will pursue a rigorous training program to address gaps in his knowledge and allow him to accomplish the aims of this K25 award. The training objectives will focus on Dr. Eteleeb’s transition into the field of AD and aging and include 1) acquire a strong foundation in neurology, clinical, and neuropathology aspects of AD and related dementias, 2) learn and employ novel ways to identify molecular subtypes of AD and specific biomarkers associated with cognitive function, followed by validation techniques in humans and model organisms, 3) gain in-depth understanding of the genetic and epigenetic factors affecting AD molecular subtypes, and 4) develop leadership and professional skills for leading an independent lab focused on transitional research in AD and aging. These objectives will be accomplished through courses, workshops, seminars, journal clubs, conferences, and feedback from the advisory committee. The primary objective of the proposed research is to identify and characterize molecular subtypes of AD associated with cognitive function by employing an innovative approach that combines cross-omics and machine learning. AD is a heterogeneous neurodegenerative disorder affecting over 50 million individuals worldwide. One critical and often overlooked factor impeding development of effective treatment for AD is the clinical and molecular heterogeneity among AD patients. Cross-omics approaches integrate heterogeneous molecular profiles to study not only how these profiles change in AD, but also uncover relationships and correlations between biological molecules. The specific proposed research aims are 1) identify and characterize cross-omics AD molecular subtypes associated with cognitive function conserved across cohorts and brain regions, 2) Determine whether molecular subtypes are specific to AD or present in other neurodegenerative disorders, and 3) identify CSF/blood-based biomarkers from AD molecular subtypes. The results will reveal insights into AD subpopulations and identify AD molecular subtypes, pathways, and biomarkers, which could lead to new pathways for implementing precision medicine and developing novel therapeutics for AD. Successful completion of this award will facilitate future independent funding to leverage cross-omics to deepen our understanding of the molecular mechanisms of AD progression.

项目概要/摘要 这个指导性职业发展奖的目标是提供一个强有力的生物学培训课程 Eteleeb 博士博士的神经退行性疾病和衰老研究是一位在基因组学、组学、 和机器学习，使他能够过渡到华盛顿大学学院的独立研究。 医学是全国公认的医学研究领导者，为医学研究提供了优越的环境 候选人与阿尔茨海默病（AD）和衰老领域的世界知名人士一起接受培训。 提案将在一支优秀的跨学科领导团队的指导下进行，该团队的领导者具有广泛的经验 以及 AD、衰老、神经科学、遗传学和跨组学方面的互补专业知识，他们致力于 支持 Eteleeb 博士在该奖项的指导下完成其研究和培训目标。 作为该团队的一员，Eteleeb 博士将接受严格的培训计划，以弥补他的知识差距，并让他能够 为了实现该 K25 奖项的目标，培训目标将集中于 Eteleeb 博士向医学界的过渡。 AD 和衰老领域，包括 1) 在神经病学、临床和神经病理学方面获得坚实的基础 AD 和相关痴呆症的各个方面，2) 学习并采用新方法来识别 AD 的分子亚型和 与认知功能相关的特定生物标志物，然后是人类和模型的验证技术 生物体，3）深入了解影响AD分子的遗传和表观遗传因素 子类型，以及 4) 培养领导力和专业技能，以领导一个专注于 AD 和老龄化方面的过渡性研究将通过课程、研讨会、 研讨会、期刊俱乐部、会议以及咨询委员会的反馈。 拟议的研究旨在识别和表征与认知功能相关的 AD 分子亚型 通过采用结合跨组学和机器学习的创新方法，AD 是一种异构的方法。 神经退行性疾病影响着全球超过 5000 万人，这是一种严重且经常被忽视的疾病。 阻碍 AD 有效治疗方法开发的因素是 AD 之间的临床和分子异质性 跨组学方法整合异质分子图谱不仅可以研究这些患者的情况。 AD 的概况发生变化，但也揭示了生物分子之间的关系和相关性。 拟议的研究目标是 1) 识别和表征与相关的跨组学 AD 分子亚型 认知功能区域在群体和大脑中保守，2) 确定分子亚型是否是 特定于 AD 或存在于其他神经退行性疾病中，以及 3) 识别脑脊液/血液生物标志物 AD 分子亚型的结果将揭示 AD 亚群的见解并识别 AD 分子。 亚型、途径和生物标志物，这可能会导致实施精准医疗的新途径 成功完成该奖项将有助于未来的独立。 资助利用跨组学来加深我们对 AD 进展分子机制的理解。