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

项目摘要/摘要：体细胞线粒体DNA突变对从 从正常衰老到阿尔茨海默病。 候选人和培训：桑切斯-孔特雷拉斯博士是医学博士，博士，系代理讲师 华盛顿大学(UW)实验室医学和病理学。她的研究目标是 了解线粒体DNA(MtDNA)体细胞突变对线粒体的影响 在衰老过程中发挥作用，并进一步将这些与致病线粒体DNA突变区分开来 阿尔茨海默病(AD)的线粒体功能障碍。为了发展她的研究领域，桑切斯博士- 孔特雷拉斯将在双链测序和神经变性方面应用她的专业知识，同时她将获得技能 在程序中测量线粒体生理学并进行数据分析。本次培训的重点将是 线粒体衰老的基础生物学由四位线粒体遗传学和 生物学、神经病理学和衰老和AD的活体模型，并沉浸在一个作为领导者的研究小组中 在该国的老龄化和AD研究中。 研究：AD患者大脑中发现线粒体DNA体细胞突变和线粒体功能障碍 病人。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 阿尔茨海默病从正常到致病。这项研究的主要假设是体细胞mtDNA异常突变。 在AD的临床前和早期阶段增加，并对线粒体和突触起作用 功能障碍和AD病理的恶化。这一假设将在两个目标上得到检验。在目标1中，Pre- 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病理学相关。在目标2中，对体细胞线粒体DNA突变和线粒体进行了系统评价 通过在多个年龄段增加体细胞突变，将在小鼠大脑中执行这一功能 突变体mito-APOBEC1转基因。最后，将在两个模型中研究体细胞突变在AD中的影响 主要神经病理成分：淀粉样变性和肌萎缩侧索硬化症。这两种方法将 有助于理解内嗅皮层和海马体细胞数量增加时的反应 阿尔茨海默病进展早期的突变和有丝分裂障碍。 职业发展计划：此K01奖项的执行旨在确保Sanchez-Contrera博士 成功地过渡到她所在系的独立教员职位。为了实现这一目标，一个结构化的计划是 这包括她的机构和她的部门承诺支持她的努力，一个强有力的 指导委员会，巩固战略协作和关键的业绩 将在老龄化领域取得重大进展的试验性协议，这将是 为本次K01结束时提交的R21和R01奠定基础。

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.