A Mouse Model of the Human 18q Deletion Syndrome

描述（由申请人提供）：人类染色体畸变导致相当多的疾病，并且将越来越多地使用更灵敏的方法和工具来分析人类染色体，从而确定染色体畸变与“特发性”病例之间的因果关系。随着人类和小鼠基因组测序、基因工程和DNA操作策略的进步，现在有可能在相对较短的时间内建立小鼠人类染色体畸变的模型，并找出小鼠发病的潜在机制。从小鼠模型中获得的知识然后被带回临床，希望能更好地诊断，预后，并可能改善患者的病情，如果不是治疗。 该项目将针对最近的技术进步，以产生人类18 q缺失综合征的小鼠模型。18 q-综合征是末端缺失综合征的一个例子，18号染色体长臂末端部分的单倍不足导致智力迟钝和多种先天性畸形。该小鼠模型的产生将证明在小鼠中快速工程化任何人类染色体畸变的可能性。对生成的小鼠模型的分析将证明其作为一种资源对广泛的研究问题的有用性，包括发育和发育障碍、颅面障碍以及神经和精神疾病。 具体目标包括：（1）通过Cre重组酶介导的胚胎干细胞切除，产生模拟人18 q缺失综合征的小鼠染色体18节段缺失;（2）通过将靶向ES细胞注射到胚泡中，产生携带18 q缺失的小鼠品系;和（3）根据18 q缺失综合征患者所显示的表型特征，表征18 q-小鼠突变体。 我们的目标是设计一种小鼠突变体，使我们能够模拟人类18 q缺失综合征。生产这种突变体是关键的第一步。该模型预计将允许-在进一步的研究项目-探索这种综合征的疾病发病机制。最终，18 q综合征小鼠模型将用于将知识带回临床。

DESCRIPTION (provided by applicant): Human chromosomal aberrations contribute to a considerable number of diseases and a causative relationship between chromosomal aberrations and "idiopathic" cases will increasingly be established with more sensitive methods and tools for analyzing human chromosomes. With the advances made in sequencing both the human and mouse genome, in genetic engineering, and in DNA manipulation strategies it is now possible - in a relatively short time - to model cases of human chromosomal aberrations in the mouse and work out the underlying mechanisms of pathogenesis in the mouse. Knowledge gained from the mouse model is then taken back to the clinic with hopefully better diagnosis, prognosis, and possibly improvements of the patients' conditions, if not treatment. This project will target the recent technological advances to generate a mouse model of the human 18q deletion syndrome. The 18q- syndrome is an example of a terminal deletion syndrome with haploinsufficiency of the terminal part of the long arm of chromosome 18 resulting in mental retardation and multiple congenital malformations. The generation of this mouse model will demonstrate the possibility of speedily engineering any human chromosomal aberration in mouse. The analysis of the generated mouse model will demonstrate its usefulness as a resource to a wide array of research problems, including development and developmental disorders, cranio-facial disorders, and neurological and mental illness. The Specific Aims include: (1) creating a mouse chromosome 18 segmental deletion modeling the human 18q deletion syndrome by Cre recombinase mediated excision in embryonic stem cells; (2) generating a mouse strain carrying the 18q deletion by injection of targeted ES cells into blastocysts; and (3) characterizing 18q- mouse mutants with respect to the phenotypic features displayed by patients with the 18q deletion syndrome. Our goal for this proposal is to engineer a mouse mutant that will allow us to model the human 18q deletion syndrome. The production of this mutant is the critical first step. This model is anticipated to allow - in further research projects - to explore the disease pathogenesis of this syndrome. Ultimately, the 18qsyndrome mouse model will be used to take knowledge back to the clinic.