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.

项目总结/摘要 这个指导职业发展奖的目标是提供一个强大的生物学培训课程， 神经退行性变和衰老，在基因组学，组学， 和机器学习，使他能够过渡到研究独立。华盛顿大学 医学是全国公认的医学研究的领导者，并提供了一个优秀的环境， 候选人的培训与世界知名人士在阿尔茨海默病（AD）和老龄化领域。这 建议将在一个优秀的跨学科领导团队的指导下进行， 以及AD、衰老、神经科学、遗传学和交叉组学方面的互补专业知识， 支持Eteleeb博士完成本奖项中提出的研究和培训目标。为指导 在这个团队中，Eteleeb博士将进行严格的培训计划，以解决他的知识差距， 实现K25奖项的目标。培训目标将侧重于Eteleeb博士过渡到 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和相关痴呆的方面，2）学习和采用新的方法来识别AD的分子亚型， 与认知功能相关的特定生物标志物，随后是人类和模型中的验证技术 生物，3）深入了解影响AD分子的遗传和表观遗传因素 亚型，以及4）发展领导和专业技能，领导一个独立的实验室，重点是 AD和衰老的过渡性研究。这些目标将通过课程、讲习班、 研讨会、期刊俱乐部、会议和咨询委员会的反馈。的主要目的 拟议的研究是确定和表征与认知功能相关的AD分子亚型 通过采用结合交叉组学和机器学习的创新方法。AD是一种异构的 神经退行性疾病影响全球超过5000万人。一个关键的，经常被忽视的 阻碍AD有效治疗的因素是AD的临床和分子异质性 患者交叉组学方法整合了异质性分子谱，不仅研究了这些分子如何在细胞中表达， 在AD中，谱改变，但也揭示了生物分子之间的关系和相关性。具体 建议的研究目标是：1）识别和表征与以下相关的交叉组学AD分子亚型： 认知功能在群组和脑区域之间保持不变，2）确定分子亚型是否是 特异于AD或存在于其他神经变性疾病中，和3）鉴定基于CSF/血液的生物标志物 从AD分子亚型。这些结果将揭示AD亚群的见解，并确定AD分子 亚型，途径和生物标志物，这可能导致实施精准医学的新途径 并开发新的治疗AD的药物。成功完成此奖项将有助于未来的独立 资助利用交叉组学来加深我们对AD进展的分子机制的理解。