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了相当多的疾病，随着对人类染色体分析的更敏感的方法和工具的使用，染色体畸变与“特发性”病例之间的因果关系将越来越多地建立起来。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——在小鼠身上建立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随后被带回诊所，希望能得到更好的诊断、预后，并可能改善患者的病情，如果不能治疗的话。

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.