Modifier Genes for Ectopic Mineralization

异位矿化的修饰基因

• 批准号: 8699949
• 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/8699949
• 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; 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; in vivo; insight; loss of function mutation; member; mineralization; mortality; mouse model; multidisciplinary; new therapeutic target; novel; novel diagnostics; protein expression; public health relevance; 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）：此修订的指导职业发展奖申请（K 01）围绕弹性假黄瘤（PXE），孟德尔常染色体隐性遗传疾病的特点是异位矿化的结缔组织在各种器官，包括皮肤，眼睛和心血管系统，具有相当大的发病率和死亡率。PXE是由ABCC 6基因突变引起的，该基因编码一种推定的跨膜转运蛋白ABCC 6，ABCC 6主要在肝脏中表达，在肾脏中表达程度较低，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。 本申请将扩展申请人Qiaoli Li博士的基线技能，以解决使用小鼠遗传方法鉴定和表征异位皮肤矿化（PXE的主要特征）的主要和次要修饰基因的总体目标。将严重受累的KK/HIJ小鼠与未受影响的C57 BL/6 J小鼠（其是Abcc 6等位基因突变的野生型）杂交，以及将严重受累的KK/HIJ小鼠与未受影响的DBA/2 J小鼠（其具有与KK/HIJ小鼠相同的Abcc 6等位基因突变）杂交，允许检查它们的N2后代用于定量性状基因座（QTL）分析，以鉴定潜在地修饰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提供新的见解的分子途径，导致表型变异的PXE，与涉及异位矿化的常见疾病。了解这些途径有望为开发新的药理学方法提供机会，以改善甚至治愈这些目前难以治愈的疾病。 Jouni Uitto博士和John P. Sundberg博士加入导师团队为李博士提供了一个绝佳的机会，可以利用他们的专业知识，了解他们的各种技能，并利用他们积累的资源。这些提供资源，立即利用这些研究，这将支持申请人的进展成为一个独立的研究人员。