Modifier Genes for Ectopic Mineralization

描述（由申请人提供）：本修订后的指导职业发展奖申请（K01）是关于弹性假性黄瘤（PXE）的，这是一种孟德尔常染色体隐性遗传病，其特征是多种器官结缔组织的异位矿化，包括皮肤、眼睛和心血管系统，具有相当高的发病率和死亡率。PXE是由ABCC6基因突变引起的，该基因编码一种假定的跨膜转运蛋白ABCC6， ABCC6主要在肝脏中表达，在肾脏中表达较少，在受PXE影响的组织中表达水平非常低。增加这种疾病的复杂性是观察到有相当大的家族间和家族内异质性。遗传因素，环境和生活方式变量也调节疾病的进展和最终结果。本申请将扩展申请人Li Qiaoli博士的基本技能，以解决使用小鼠遗传方法识别和表征PXE的主要特征异位皮肤矿化的主要和次要修饰基因的总体目标。将严重感染的KK/HIJ小鼠与未受影响的C57BL/6J野生型小鼠进行杂交，将严重感染的KK/HIJ小鼠与未受影响的DBA/2J小鼠进行杂交，这些小鼠具有与KK/HIJ小鼠相同的Abcc6等位基因突变，可以对它们的N2后代进行定量性状位点（QTL）分析，以确定可能改变皮肤矿化表型的修饰基因。候选基因的体内功能表征将证明其在异位矿化过程中的重要性。预计这项研究的结果将为导致PXE表型变异的分子途径提供新的见解，并与涉及异位矿化的常见疾病相关。了解这些途径有望为开发新的药理学方法提供机会，以改善甚至可能治愈这些目前难以治疗的疾病。拥有两个博士学位。指导团队的Jouni Uitto和John P. Sundberg为李博士提供了一个利用他们的专业知识、学习他们不同技能的绝佳机会，并利用他们积累的资源。这些为这些研究提供了立即利用的资源，这将支持申请人成为一名独立研究人员。

DESCRIPTION (provided by applicant): This revised Mentored Career Development Award application (K01) revolves around pseudoxanthoma elasticum (PXE), a Mendelian autosomal recessive disorder characterized by ectopic mineralization of connective tissues in a variety of organs, including the skin, eyes, and the cardiovascular system, with considerable morbidity and mortality. PXE results from mutations in the ABCC6 gene which encodes a putative transmembrane transporter protein, ABCC6, which is expressed primarily in the liver, to a lesser extent in kidneys, and at very low levels, if at all, in tissues affected by PXE. Adding to the complexity of this disorder are the observations that there is considerable inter- and intra-familil heterogeneity. Genetic factors, environmental, and life style variables also modulate the progression and eventual outcome of the disease. This application will expand upon baseline skills of the applicant, Dr. Qiaoli Li, to address the overall goal of identifying and characterizig the major and minor modifier genes of ectopic cutaneous mineralization, a predominant feature of PXE, using mouse genetic approaches. Crossing the severely affected KK/HIJ mice with unaffected C57BL/6J mice which are wild type for the Abcc6 allelic mutation, and crossing the severely affected KK/HIJ mice with unaffected DBA/2J mice with the same Abcc6 allelic mutation as KK/HIJ mice, allows examination of their N2 progeny for Quantitative Trait Locus (QTL) analysis to identify modifier genes that potentially modifies the cutaneous mineralization phenotype. Functional in vivo characterization of the candidate genes will prove their importance in ectopic mineralization process. It is expected that the results of this study will provide novel insights into the molecular pathways leading to phenotypic variability in PXE, with relevance to common disorders involving ectopic mineralization. Understanding such pathways is expected to provide opportunities for the development of novel pharmacologic approaches to ameliorate, and perhaps cure, these currently intractable conditions. Having both Drs. Jouni Uitto and John P. Sundberg on the mentoring team provides Dr. Li with an outstanding opportunity to take advantage of their expertise, learn about their diverse skill sets, and to utilze resources they have accumulated. These provide resources to immediately utilize for these studies which will support the applicant's progress into becoming an independent researcher.