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：
Marco Seandel
金额：
$ 252.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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（由申请人提供）：多种疾病，包括自闭症，精神分裂症，肌肉症，Apert综合征和某些癌症在年龄较大的父亲出生的人中更为常见。该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）中产生了大量的从头等位基因。人睾丸中突变的精子干细胞（SSC）的阳性选择可能使异常精子能够为下一代贡献这种从头突变等位基因，从而导致观察到的病理学。我们正在通过在体内与移植一起操纵培养成人SSC的培养物来解决这一假设，以便为PAES的假定机制提供直接的实验证据。该项目的目标是解决与特定疾病相关突变的机制，并制定一项方案，以发现和迅速验证新型突变。为了设计策略以防止或治疗遗传疾病，对它们的分子起源的理解将非常有价值。本文所述的实验将支持PAE的常见机制，并表明PAE疾病可以被视为原型干细胞疾病。一种对突变等位基因发现的体外建模方法最终可以克服与多基因PAE疾病相关的遗传病变（例如自闭症）鉴定的一些技术障碍，否则需要大量的人类数据集。通过提高我们对PAE疾病发病机理的细胞基础的理解和离散突变的作用，SSC的实验操作可以直接导致患者的新型治疗策略。

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：
Andrology
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.