Contribution of somatic mitochondrial DNA mutation to the transition from normal aging to Alzheimers disease

体细胞线粒体DNA突变对正常衰老向阿尔茨海默病转变的贡献

• 批准号: 10526215
• 负责人: Monica Yicette Sanchez-Contreras
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526215
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Apoptosis; Area; Automobile Driving; Autopsy; Biogenesis; Biology; Biology of Aging; Brain; Brain region; Cell Death; Cell Differentiation process; Cells; Collaborations; Country; DNA; Data Analyses; Data Science; Development; Development Plans; Disease; Doctor of Philosophy; Early Diagnosis; Electron Transport; Ensure; Evaluation; Event; Faculty; Foundations; Functional disorder; Genes; Genetic; Genome; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Institution; Knowledge; Laboratories; Lead; Link; Measures; Medicine; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic Pathway; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Mutagenesis; Mutation; Natural regeneration; Nerve Degeneration; Neurons; Neurosciences; Nuclear; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Performance; Physiology; Population; Positioning Attribute; Prevention strategy; Procedures; Process; Productivity; Protocols documentation; Publishing; Quality of life; Research; Research Personnel; Resolution; Role; Scientist; Signal Transduction; Somatic Mutation; Structure; Synapses; Synaptosomes; Tauopathies; Testing; Training; Transfection; Transgenes; Universities; Washington; adeno-associated viral vector; aged; amyloid pathology; apoB mRNA editing catalytic subunit; brain tissue; career development; design; disease stressor; early onset; entorhinal cortex; heteroplasmy; improved; in vivo Model; instructor; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mouse model; neurogenetics; neuron loss; neuropathology; normal aging; pre-clinical; prevent; programs; repaired; response; skills; synaptic function

Project Summary/Abstract: Contribution of somatic mitochondrial DNA mutation to the transition from normal aging to Alzheimer’s disease. Candidate and Training: Dr. Sanchez-Contreras is an MD, PhD, Acting Instructor in the Department of Laboratory Medicine and Pathology, University of Washington (UW). Her research is directed towards understanding the effects that somatic mutations of the mitochondrial DNA (mtDNA) have on mitochondrial function during aging, and further differentiate these from pathogenic mtDNA mutations that cause mitochondrial dysfunction in Alzheimer’s disease (AD). To develop her area of research, Dr. Sanchez- Contreras will apply her expertise in duplex sequencing and in neurodegeneration, while she will acquire skills in procedures to measure mitochondrial physiology and data analysis. This training will be focused on the underlying mitochondrial biology of aging guided by four mentors that are experts in mitochondrial genetics and biology, neuropathology and in vivo models of aging and AD and immersed in a research group that is a leader in aging and in AD research in the country. Research: Somatic mutations of the mtDNA and mitochondrial dysfunction are found in the brain of AD patients. As these findings also accompany normal aging, it is unclear what determines the departure from normal to pathogenic in AD. The main hypothesis of this study is that somatic mtDNA mutations abnormally increase at preclinical and early stages of AD, and that they contribute to mitochondrial and synaptic dysfunction, and the worsening of AD pathology. This hypothesis will be tested in two aims. In Aim 1, pre- clinical AD patients will be studied to find somatic mutations and mitochondrial and synaptic abnormalities that associate with AD pathology. In Aim 2, a systematic evaluation of somatic mtDNA mutation and mitochondrial function will be performed in the mouse brain by increasing somatic mutagenesis at multiple ages using the mutator mito-APOBEC1 transgene. Lastly, the impact of somatic mutation in AD will be studied in two models of the main neuropathological components: amyloid pathology and tauopathy. These two approaches will contribute to understanding of how the entorhinal cortex and the hippocampus respond to increasing somatic mutations and mito-dysfunction early in the progression of AD. Career Development Plan: The execution of this K01 award is designed to ensure Dr. Sanchez-Contreras’ successful transition to an independent faculty position in her department. To this aim, a structured plan is presented that includes the commitment of her institution and her department to support her efforts, a strong mentorship committee, the consolidation of strategic collaborations and the performance of crucial experimental protocols that will result in significant advancements in the field of aging and that will be the foundation for R21 and R01 submissions at the conclusion of this K01.

项目摘要/摘要：体细胞线粒体DNA突变对从 从正常衰老到老年痴呆症 候选人和培训：Sanchez-Contreras博士是医学博士，博士，系的代理讲师。 实验室医学和病理学，华盛顿大学（UW）。她的研究是针对 了解线粒体DNA（mtDNA）的体细胞突变对线粒体的影响， 在衰老过程中发挥作用，并进一步将其与致病性mtDNA突变区分开来， 阿尔茨海默病（AD）中的线粒体功能障碍。为了发展她的研究领域，桑切斯博士- 孔特雷拉斯将运用她在双重测序和神经变性方面的专业知识， 用于测量线粒体生理学和数据分析。本次培训的重点是 由四位线粒体遗传学专家指导的衰老的基本线粒体生物学， 生物学，神经病理学和衰老和AD的体内模型，并沉浸在一个领导者的研究小组中， 在老龄化和AD研究中的作用。 研究：在AD患者的大脑中发现了线粒体DNA的体细胞突变和线粒体功能障碍 患者由于这些发现也伴随着正常的衰老，目前还不清楚是什么决定了偏离 AD中正常至致病。本研究的主要假设是，体细胞线粒体DNA突变异常 在AD临床前和早期阶段增加，并且它们有助于线粒体和突触 功能障碍和AD病理学恶化。这一假设将在两个目标中得到检验。在目标1中， 将对临床AD患者进行研究，以发现体细胞突变以及线粒体和突触异常， 与AD病理学有关。目的2：系统评价体细胞线粒体DNA突变和线粒体 功能将在小鼠大脑中进行，通过使用 mutator mito-APOBEC 1转基因最后，将在两个模型中研究AD中体细胞突变的影响 主要的神经病理学成分：淀粉样蛋白病理学和tau蛋白病。这两种方法将 有助于了解内嗅皮层和海马体如何对增加的躯体 突变和有丝分裂功能障碍的早期AD的进展。 职业发展计划：K 01奖项的执行旨在确保Sanchez-Contreras博士 成功过渡到她所在部门的独立教师职位。为此，一个结构化的计划是 提出，其中包括她的机构和她的部门的承诺，以支持她的努力，一个强大的 指导委员会，巩固战略合作和业绩的关键 实验协议，将导致显着的进步，在该领域的老化，这将是 在本K 01结束时为R21和R 01提交奠定基础。