Modifier Genes for Ectopic Mineralization

异位矿化的修饰基因

基本信息

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
项目类别：
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

项目摘要

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）：这份修订后的指导职业发展奖申请 (K01) 围绕弹力假黄瘤 (PXE) 展开，这是一种孟德尔常染色体隐性遗传疾病，其特征是多种器官（包括皮肤、眼睛和身体）中结缔组织的异位矿化。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，该基因编码一种推定的跨膜转运蛋白 ABCC6，该蛋白主要在肝脏中表达，其次在肾脏中表达，并且在受 PXE 影响的组织中表达水平非常低（如果有的话）。观察到家庭间和家庭内存在相当大的异质性，这增加了这种疾病的复杂性。遗传因素、环境和生活方式变量也会调节疾病的进展和最终结果。该申请将扩展申请人李巧丽博士的基础技能，以实现使用小鼠遗传方法识别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。将严重受影响的 KK/HIJ 小鼠与未受影响的 C57BL/6J 小鼠（Abcc6 等位基因突变的野生型）杂交，并将严重受影响的 KK/HIJ 小鼠与未受影响的 DBA/2J 小鼠（具有与 KK/HIJ 小鼠相同的 Abcc6 等位基因突变）杂交，允许检查其 N2 后代进行数量性状位点 (QTL) 分析，以确定可能改变皮肤矿化的修饰基因表型。候选基因的功能体内表征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。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棘手的疾病。拥有两位博士。导师团队中的 Jouni Uitto 和 John P. Sundberg 为李博士提供了一个绝佳的机会，让他能够利用他们的专业知识、了解他们多样化的技能并利用他们积累的资源。这些提供了可立即用于这些研究的资源，这将支持申请人成为一名独立研究人员。