Modifier Genes for Ectopic Mineralization

异位矿化的修饰基因

基本信息

批准号：
9212101
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/9212101
关键词：
Address Advisory Committees Affect Age Aging Alleles 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 Eye Functional disorder Genes Genetic Genetic Crosses Genome Genotype Glean Goals Guidelines Hereditary Disease Heritability 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 Pharmacology Phenotype Process Pseudoxanthoma Elasticum Quantitative Trait Loci Rare Diseases Research Research Personnel Resources Role Scientist Severities Skin The Jackson Laboratory Tissues Training Universities Variant career career development genetic approach in vivo insight loss of function mutation member mineralization mortality mouse model multidisciplinary new therapeutic target novel novel diagnostics patient subsets predicting response prognostic protein expression public health relevance skills skin disorder therapeutic development therapy development tool transcriptome treatment response

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）：该修订后的职业发展奖应用程序（K01）围绕Pseudoxanthoma Elasticum（PXE），这是一种Mendelian常染色体常染色体隐性疾病，其特征在于各种器官，包括皮肤，眼睛，以及具有巨大系统的杂质系统的连接组织的异位矿物质矿物质。 PXE是由ABCC6基因突变引起的，该突变编码了假定的跨膜转运蛋白ABCC6，该蛋白ABCC6主要在肝脏中表达，在肾脏的程度较小，并且在受PXE影响的组织中（如果有的话）。这种疾病的复杂性增加的是，观察到存在相当大的 - 氨基元内异质性。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。该应用程序将扩大申请人的基线技能，Qiaoli Li博士，以解决使用小鼠遗传方法的异位皮肤矿化的主要和次要修饰剂基因的总体目标，这是PXE的主要特征。将严重影响的KK/HIJ小鼠与未受影响的C57BL/6J小鼠穿越ABCC6等位基因突变是野生类型的，并用不受影响的DBA/2J小鼠跨越了严重影响的KK/HIJ小鼠。这可能会改变皮肤矿化表型。候选基因的体内表征功能性表征将证明它们在异位矿化过程中的重要性。可以预期，这项研究的结果将提供对导致PXE表型变异性的分子途径的新见解，与涉及异位矿化的常见疾病有关。预计理解这种途径将为开发新型药理方法的发展提供机会，以改善这些目前棘手的疾病，从而治愈这些途径。都有两个dr。指导团队的Jouni Uitto和John P. Sundberg为Li博士提供了一个出色的机会，可以利用他们的专业知识，了解他们的多样化技能，并提供他们积累的资源。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独立研究人员的进步。