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iPSC Modeling of AD Using Progerin

iPSC Modeling of AD Using Progerin
使用 Progerin 对 AD 进行 iPSC 建模
批准号:
9926785
负责人:
SALLY TEMPLE
金额:
$40.31万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-01 至 2022-04-30

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英文摘要
Project Summary/Abstract Age is the strongest risk factor for Alzheimer's disease (AD). However, cell and animal models of AD fail to recapitulate human aging and fail to capture key aspects of disease pathology. Our long-term goal is to understand how aging contributes to AD pathogenesis. Therefore, we propose to develop an induced pluripotent stem cell (iPSC)-based model of AD that incorporates accelerated aging, with the objective of more robustly modeling AD onset and progression. Recent findings indicate that perturbations in lamin A biology may contribute to AD. In preliminary studies, we have found a significant increase in LMNA, the gene that encodes the nuclear envelope protein lamin A, and a significant decrease in ZMPSTE24, a prelamin A processing enzyme, in autopsy-confirmed AD brain tissue and in laser-dissected neurons from AD brains compared to age-matched controls. We predict that these changes in LMNA and ZMPSTE24 levels would cause an increase in farnesylated prelamin A, which has been shown to drive accelerated aging phenotypes, including acquisition of an abnormal nuclear lamina, and impairments in nucleocytoplasic compartmentation, chromatin organization and gene expression similar to the accumulation of the LMNA isoform progerin. We hypothesize that forced expression of prelamin A or progerin accelerates age-associated changes and disease phenotypes in iPSC-cortical cells derived from AD patients. First, we will determine whether lamin A expression and processing are perturbed in AD brains and AD-predisposed iPSC-cortical cells. We will then determine whether forced progerin expression causes aging-related dysfunction in AD-predisposed iPSC- cortical neurons and astrocytes. Finally, we will define and quantify the effects of forced progerin expression on cell phenotypes related to AD pathology, including Aβ and tau secretion, aggregation and turnover, in iPSC-2D cortical cells and in 3D forebrain organoids. The results from this study will determine whether perturbations in lamin A biology are associated with AD, and potentially contribute to AD pathogenesis, and will establish a novel model incorporating lamin A-related aging parameters in a human AD iPSC-cortical cell model. These findings will open novel avenues for investigating the contribution of aging to the disease mechanisms underlying AD pathology and will advance the development of in vitro models of AD to aid in the design and validation of potential therapeutic strategies.
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    10337229
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iPSC Modeling of AD Using Progerin
  • 批准号:
    10153610
  • 项目类别:
  • 资助金额:
    $40.31万
  • 财政年份:
    2017
  • 负责人:
    SALLY TEMPLE
  • 依托单位:
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