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: 10704620
• 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/10704620
• 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; Dementia; Development; Development Plans; Disease; Doctor of Philosophy; Early Diagnosis; Electron Transport; Ensure; Evaluation; Event; Faculty; Foundations; Functional disorder; Genes; Genetic; Genome; Goals; Health; Hippocampus; 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; Recycling; 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; skill acquisition; 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 正常衰老导致阿尔茨海默病。 候选人和培训：Sanchez-Contreras 博士是医学博士、哲学博士、医学系代理讲师 华盛顿大学 (UW) 实验医学和病理学。她的研究方向是 了解线粒体 DNA (mtDNA) 的体细胞突变对线粒体的影响 衰老过程中的功能，并进一步将其与导致衰老的致病性 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- Contreras 将运用她在双链测序和神经退行性疾病方面的专业知识，同时她还将获得技能 测量线粒体生理学和数据分析的程序。本次培训将重点关注 由四位线粒体遗传学专家和导师指导的线粒体衰老生物学基础 生物学、神经病理学以及衰老和 AD 的体内模型，并沉浸在领先的研究小组中 在该国的老龄化和AD研究方面。 研究：AD 患者大脑中发现 mtDNA 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衰老，目前尚不清楚是什么决定了这种偏离 AD 中正常到致病。本研究的主要假设是体细胞线粒体DNA突变异常 在 AD 的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 病理恶化。该假设将在两个目标上进行检验。在目标 1 中，预 将研究临床 AD 患者以发现体细胞突变以及线粒体和突触异常 与 AD 病理有关。在目标 2 中，系统评估体细胞 mtDNA 突变和线粒体 通过使用以下方法在多个年龄段增加体细胞诱变，在小鼠大脑中发挥功能 突变 mito-APOBEC1 转基因。最后，体细胞突变对 AD 的影响将在两个模型中进行研究 主要神经病理学成分：淀粉样蛋白病理学和 tau 蛋白病。这两种方法将 有助于理解内嗅皮层和海马体如何应对增加的躯体细胞 AD 进展早期的突变和线粒体功能障碍。 职业发展计划：K01奖项的执行旨在确保Sanchez-Contreras博士的职业发展计划 成功过渡到她所在部门的独立教职职位。为了这个目标，一个结构化的计划是 提出了包括她的机构和部门支持她的努力的承诺，一个强有力的 导师委员会、巩固战略合作和关键绩效 实验方案将在衰老领域带来重大进展，这将是 在本 K01 结束时为 R21 和 R01 提交奠定基础。