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

基本信息

项目摘要

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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Monica Yicette Sanchez-Contreras其他文献

Monica Yicette Sanchez-Contreras的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Monica Yicette Sanchez-Contreras', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 12.14万
  • 项目类别:
Mitochondrial DNA mutations in the renal cortex to elucidate cell-specific mechanisms of mitochondrial dysfunction in tubules and glomeruli
肾皮质线粒体 DNA 突变阐明肾小管和肾小球线粒体功能障碍的细胞特异性机制
  • 批准号:
    10190112
  • 财政年份:
    2021
  • 资助金额:
    $ 12.14万
  • 项目类别:
Mitochondrial DNA mutations in the renal cortex to elucidate cell-specific mechanisms of mitochondrial dysfunction in tubules and glomeruli
肾皮质线粒体 DNA 突变阐明肾小管和肾小球线粒体功能障碍的细胞特异性机制
  • 批准号:
    10357869
  • 财政年份:
    2021
  • 资助金额:
    $ 12.14万
  • 项目类别:
Mitochondrial DNA mutations in the renal cortex to elucidate cell-specific mechanisms of mitochondrial dysfunction in tubules and glomeruli
肾皮质线粒体 DNA 突变阐明肾小管和肾小球线粒体功能障碍的细胞特异性机制
  • 批准号:
    10581517
  • 财政年份:
    2021
  • 资助金额:
    $ 12.14万
  • 项目类别:

相似海外基金

Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
  • 批准号:
    24K18114
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
  • 批准号:
    498288
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
  • 批准号:
    10089306
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Collaborative R&D
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
  • 批准号:
    498310
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
  • 批准号:
    23K20339
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
  • 批准号:
    2740736
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
  • 批准号:
    2406592
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
  • 批准号:
    2305890
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
  • 批准号:
    23K20355
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
  • 批准号:
    23K24782
  • 财政年份:
    2024
  • 资助金额:
    $ 12.14万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了