Clonal competition in stem cells as a driver of paternal age effect diseases

干细胞的克隆竞争是父亲年龄效应疾病的驱动因素

基本信息

  • 批准号:
    8570427
  • 负责人:
  • 金额:
    $ 252.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-19 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A variety of disorders, including autism, schizophrenia, achondroplasia, Apert Syndrome, and some cancers are more common in those born to older fathers. This association has been referred to as the paternal age effect (PAE). High-throughput, low-cost DNA sequencing techniques have recently yielded very large numbers of candidate de novo alleles in some of these diseases (e.g., autism and schizophrenia). Positive selection of mutant spermatogonial stem cells (SSCs) in the human testis may enable aberrant sperm to contribute such de novo mutant alleles to the next generation, resulting in the observed pathology. We are addressing this hypothesis by manipulating adult SSCs in culture, in conjunction with transplantation in vivo, in order to provide direct, experimental evidence for a putative mechanism of PAEs. The goals of the project are to address the mechanisms of specific disease-associated mutations and develop a protocol to discover and rapidly validate novel mutations. In order to design strategies to prevent or treat inherited disorders, an understanding of their molecular origins will be extremely valuable. The experiments described herein would support a common mechanism for PAEs and would show that PAE diseases could be considered prototypical stem cell-based diseases. An in vitro modeling approach to mutant allele discovery could eventually overcome some of the technical barriers to identification of genetic lesions associated with multigenic PAE diseases (e.g., autism), which otherwise requires large human data sets. By improving our understanding of the cellular basis for PAE disease pathogenesis and the roles of discrete mutations, experimental manipulation of SSCs could lead directly to novel therapeutic strategies for patients.
描述(申请人提供):各种疾病,包括自闭症、精神分裂症、软骨发育不全、Apert综合征和一些癌症,在那些父亲年龄较大的孩子中更常见。这种关联被称为父亲年龄效应(PAE)。高通量、低成本的DNA测序技术最近在其中一些疾病(例如自闭症和精神分裂症)中产生了非常大量的候选从头等位基因。人睾丸中突变的精原干细胞(SSCs)的阳性选择可能使异常精子能够将这些从头开始的突变等位基因贡献给下一代,导致观察到的病理。我们正在通过在培养中操纵成年SSCs,结合体内移植来解决这一假说,以便为PAEs的可能机制提供直接的实验证据。该项目的目标是解决特定疾病相关突变的机制,并开发一种方案来发现和快速验证新的突变。为了设计策略以防止 或者治疗遗传性疾病,了解它们的分子起源将是非常有价值的。这里描述的实验将支持PAEs的共同机制,并将表明PAE疾病可以被认为是典型的干细胞疾病。发现突变等位基因的体外建模方法最终可能克服识别与多基因PAE疾病(例如自闭症)相关的遗传损伤的一些技术障碍,否则需要大量的人类数据集。通过提高我们对PAE疾病发病机制的细胞学基础和离散突变的作用的理解,SSCs的实验操作可能直接为患者带来新的治疗策略。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Evaluation of candidate spermatogonial markers ID4 and GPR125 in testes of adult human cadaveric organ donors.
  • DOI:
    10.1111/j.2047-2927.2014.00226.x
  • 发表时间:
    2014-07
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Sachs C;Robinson BD;Andres Martin L;Webster T;Gilbert M;Lo HY;Rafii S;Ng CK;Seandel M
  • 通讯作者:
    Seandel M
Faithful Artificial Chromosome Propagation Using Spermatogonial Stem Cells.
  • DOI:
    10.1016/j.tig.2017.10.003
  • 发表时间:
    2017-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yamada M;Seandel M
  • 通讯作者:
    Seandel M
Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras.
诱导过度活跃的 Hras 后成体精原干细胞的功能稳健性。
  • DOI:
    10.1371/journal.pgen.1008139
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Yamada,Makiko;Cai,Winson;Martin,LauraA;N'Tumba-Byn,Thierry;Seandel,Marco
  • 通讯作者:
    Seandel,Marco
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Marco Seandel其他文献

Marco Seandel的其他文献

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{{ truncateString('Marco Seandel', 18)}}的其他基金

Negative feedback regulation of growth factor signaling in adult spermatogonial stem cells
成体精原干细胞生长因子信号传导的负反馈调节
  • 批准号:
    10361426
  • 财政年份:
    2021
  • 资助金额:
    $ 252.75万
  • 项目类别:

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