Modifier Genes for Ectopic Mineralization

异位矿化的修饰基因

• 批准号: 8816033
• 负责人: Qiaoli Li
• 金额: $ 12.68万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816033
• 关键词: Address; Advisory Committees; Affect; Age; Aging; Backcrossings; Binding; Biomedical Research; Blood Vessels; Calcinosis; Candidate Disease Gene; Cardiovascular system; Carrier Proteins; Characteristics; Clinical; Connective Tissue; Cutaneous; Dermis; Development; Disease; Disease Outcome; Environment; Environmental Risk Factor; Eye; Functional disorder; Gene Expression Profile; Genes; Genetic; Genetic Crosses; Genome; Genotype; Glean; Goals; Guidelines; Health; Hereditary Disease; Heterogeneity; Human; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Inflammatory; K-Series Research Career Programs; Kidney; Knockout Mice; Knowledge; Learning; Life Style; Liver; Mentors; Mentorship; Minor; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Organ; Pathway interactions; Patients; Phenotype; Process; Pseudoxanthoma Elasticum; Quantitative Trait Loci; Rare Diseases; Research; Research Personnel; Resources; Role; Scientist; Severities; Skin; System; The Jackson Laboratory; Therapeutic Intervention; Tissues; Training; Universities; Variant; base; career; career development; genetic approach; in vivo; insight; loss of function mutation; member; mineralization; mortality; mouse model; multidisciplinary; new therapeutic target; novel; novel diagnostics; protein expression; response; skills; skin disorder; tool

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.

描述(由申请人提供)：本次修订的导师职业发展奖申请(K01)围绕着弹性假黄瘤(PXE)，这是一种孟德尔常染色体隐性遗传病，其特征是各种器官中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，该蛋白主要在肝脏表达，在肾脏中表达较少，在受PXE影响的组织中表达水平很低。除了这种疾病的复杂性，还有观察到有相当大的家庭间和家庭内的异质性。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。本申请将扩展申请者李巧丽博士的基线技能，以解决使用小鼠遗传学方法识别和表征异位皮肤矿化的主要和次要修饰基因的总体目标，异位皮肤矿化是PXE的主要特征。将受严重影响的KK/HIJ小鼠与未受影响的C57BL/6J小鼠(野生型Abcc6等位基因突变)杂交，并将受严重影响的KK/HIJ小鼠与具有与KK/HIJ小鼠相同的Abcc6等位基因突变的未受影响的DBA/2J小鼠杂交，允许检查其N2后代以进行数量性状基因(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鉴定将证明它们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。对这些途径的了解有望为开发新的药理学方法来改善甚至治愈这些目前难以治愈的疾病提供机会。Jouni Uitto博士和John P.Sundberg博士都加入了指导团队，这为李博士提供了一个利用他们的专业知识、了解他们的不同技能以及利用他们积累的资源的绝佳机会。这些资源可立即用于这些研究，这将有助于申请人成为独立研究人员。