Novel strategies for induction of aging in human iPSC-derived lineages towards improved models of late-onset diseases

诱导人类 iPSC 衍生谱系衰老的新策略,以改进迟发性疾病模型

基本信息

  • 批准号:
    9924425
  • 负责人:
  • 金额:
    $ 56.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-15 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary The primary risk factor for most neurodegenerative diseases and many other human ailments such as cancer is old age. A major challenge in studying late-onset diseases is the accurate representation of the aging context in both in vitro and in vivo models of the disease. This is due in part to a lack of understanding of the cellular and molecular characteristics of the aging process. We previously defined a set of cellular changes associated with aging in cells from old donors and demonstrated that these age-related hallmarks are restored to a youthful state through reprogramming into induced pluripotent stem cells (iPSC) and maintained in such “rejuvenated” state upon re-differentiation into iPSC-derived cells. This phenomenon, while fascinating from a scientific perspective, also represents a concrete barrier for the use of iPSC for studying age-dependent disorders. Our group demonstrated that these aging characteristics can be reintroduced into iPSC-derived cells through simple expression of progerin, a mutant form of the lamin A (LMNA) protein that is responsible for the premature aging disorder Hutchinson-Gilford Progeria. However, inducing cellular age using a disease-causing factor may not be a faithful representation of physiological aging and potentially lead to pathological artifacts in modeling aging-related diseases. It is therefore necessary to develop a cellular model that will accurately reproduce the physiological aging context. Our hypothesis, supported by promising preliminary results, is that cellular aging is promoted by specific genetic and epigenetic changes that can be utilized to trigger an aged cellular state in models of late-onset disease. Here, we propose to develop a new approach for modeling age in iPSC-derived neuronal lineages in three specific steps. First, we aim to generate a comprehensive characterization of genetic and epigenetic features of aged cells using primary fibroblasts and brain tissues from young and old donors, which will provide genomic aging signatures of different cell lineages. We will then monitor those signatures during reprogramming and identify candidate determinants of cellular age. We will validate these signatures by targeted experiments as well as on independent samples. Second, using a combination of our previously identified cellular hallmarks of aging in conjunction with the newly identified genetic and epigenetic aging markers we will design optimal strategies to induce cellular aging. Third, we will use these strategies to study the impact of cellular age on the progression and pathology of Parkinson disease (PD) using iPSC-derived dopamine neurons from patients with genetic forms of PD. These will both be used for in vitro studies characterizing cellular PD manifestations as well as in vivo upon transplantation into PD mouse models to assess the impact of induced aging on cellular behavior and function in vivo. The results from this study will provide a more comprehensive understanding of the genetic and epigenetic changes that underlie human aging and importantly, provide a methodology to induce aging context in iPSC models of human diseases.
项目摘要 大多数神经退行性疾病和许多其他人类疾病(例如癌症)的主要危险因素 是老年人。 在体外和体内模型中,这部分是由于对您的理解 衰老过程的细胞和分子特征。 与旧供体的细胞衰老相关并证明这些相关标志已恢复 通过重新编程到诱导的多能干细胞(IPSC),并保持在这种状态 重新分化IPSC衍生的细胞时,“恢复活力”的状态。 科学的观点,也代表了使用IPSC研究年龄依赖性的具体障碍 我们的小组表明,这些老化特征可以重新引入IPSC衍生的细胞 通过简单表达progerin,progerin是层状A(LMNA)蛋白的突变形式。 过早的老化疾病哈钦森 - 吉尔福德的后代。 因素可能不是忠实的生理衰老的代表,并有可能导致病理伪像 与衰老相关的建模是开发蜂窝模型所必需的 再现了生理衰老的环境。 细胞衰老是通过特定的遗传和表观遗传变化来促进的,可用于触发老年 蜂窝状状态在晚期疾病的模型中。 在iPSC衍生的神经元中,我们首先要生成一个全面的 使用原发性成纤维细胞和脑组织来表征衰老细胞的遗传和表观遗传特征 来自年轻人和老年捐助者,这些捐助者将提供不同细胞Linese的基因组衰老特征。 监测在重点期间的签名,并确定细胞年龄的候选因素 使用目标体验和独立样本来验证签名 我们先前确定的衰老的细胞标志与新确定的结合 遗传和表观遗传衰老标记我们将设计最佳的策略来诱导细胞衰老。 使用三种策略研究细胞年龄对帕金森病进度和病理的影响 (PD)使用具有遗传形式的患者的IPSC衍生的多巴胺神经元。 用于体外研究表征细胞PD表现以及移植到PD时体内的研究 小鼠模型评估诱导衰老对体内细胞行为和功能的影响。 研究的结果将为遗传和表观遗传提供更全面的理解 人类衰老的基础的变化,重要的是 人类疾病的模型。

项目成果

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Doron Betel其他文献

Doron Betel的其他文献

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{{ truncateString('Doron Betel', 18)}}的其他基金

Directing fate, subtype identity and survival in human pluripotent-derived midbrain dopamine neurons
指导人类多能源性中脑多巴胺神经元的命运、亚型识别和存活
  • 批准号:
    10378152
  • 财政年份:
    2021
  • 资助金额:
    $ 56.85万
  • 项目类别:
Directing fate, subtype identity and survival in human pluripotent-derived midbrain dopamine neurons
指导人类多能源性中脑多巴胺神经元的命运、亚型识别和存活
  • 批准号:
    10211441
  • 财政年份:
    2021
  • 资助金额:
    $ 56.85万
  • 项目类别:
Directing Fate, Subtype Identity and Survival in Human Pluripotent-Derived Midbrain Dopamine Neurons
指导人类多能源性中脑多巴胺神经元的命运、亚型识别和生存
  • 批准号:
    10596583
  • 财政年份:
    2021
  • 资助金额:
    $ 56.85万
  • 项目类别:
Novel strategies for induction of aging in human iPSC-derived lineages towards improved models of late-onset diseases
诱导人类 iPSC 衍生谱系衰老的新策略,以改进迟发性疾病模型
  • 批准号:
    10153608
  • 财政年份:
    2017
  • 资助金额:
    $ 56.85万
  • 项目类别:
Novel strategies for induction of aging in human iPSC-derived lineages towards improved models of late-onset diseases
诱导人类 iPSC 衍生谱系衰老的新策略,以改进迟发性疾病模型
  • 批准号:
    9383144
  • 财政年份:
    2017
  • 资助金额:
    $ 56.85万
  • 项目类别:

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