A conditional allele to dissect Porcn-dependent Wnt signaling in vivo

用于剖析体内 Porcn 依赖性 Wnt 信号传导的条件等位基因

基本信息

批准号：
8309767
负责人：
Lewis C Murtaugh
金额：
$ 22.43万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309767
关键词：
Acyltransferase Affect Alleles Animal Model Biochemistry Cells Characteristics Congenital Abnormality Congenital Disorders Defect Deposition Development Developmental Biology Developmental Process Disease Disease model Drosophila genus Ectoderm Embryo Engineering Enzymes Etiology Exhibits Experimental Designs Eye Family member Fatty acid glycerol esters Focal Dermal Hypoplasia Genes Genetic Genetic Models Goals Hereditary Disease Homologous Gene Human Human Genetics Human Genome Integumentary system Knock-out Knockout Mice Lateral Ligands Link Mammals Maps Mediating Mesenchymal Mesoderm Mind Modeling Modification Molecular Mus Mutant Strains Mice Mutation Operative Surgical Procedures Pathology Patients Phenotype Physiology Porcupines Production Publishing Rare Diseases Research Research Personnel Role Signal Pathway Signal Transduction Skeleton Skin Syndrome Testing Time Tissues Wnt proteins Work adipocyte differentiation autocrine base clinically relevant clinically significant human disease in vivo insight lipid biosynthesis mouse genome mouse model mutant novel paracrine precursor cell prevent programs tissue processing tissue/cell culture tool

项目摘要

DESCRIPTION (provided by applicant): The molecular underpinnings of human physiology and pathology can be sought out by the researcher, via biochemistry or forward genetics, or they can present themselves in the form of a patient seeking treatment for a common or rare congenital disorder. These dual approaches frequently converge, as in the case of the X-linked dominant human disorder focal dermal hypoplasia (FDH). This syndrome was recently mapped to the PORCN gene, the unique homolog of a Drosophila gene, porcupine, required for secretion of Wnt ligands. Although Wnts are thought to regulate many aspects of development and disease, genetic studies of ligand function in mammals are complicated by redundancy among the 19 family members. To establish a genetic tool with which to overcome this redundancy, our lab generated a conditional knockout allele of mouse Porcn and demonstrated that it provides an animal model of FDH. Building on our recently published findings, we propose here to examine two novel and disease-relevant phenotypes associated with FDH, ectopic fat deposition and incomplete body wall closure, to which our mouse model provides unique access. Our preliminary findings indicate that these phenotypes share an ectodermal etiology, which we will investigate in three specific aims: (1) determine the requirement for Porcn in production of ectodermally-expressed Wnt proteins; (2) characterize the role of Porcn-mediated Wnt signals in suppressing adipogenesis; (3) analyze Porcn mutant mice as a model for body wall closure defects. These studies will firmly establish the utility of Porcn mutants as an FDH model and as a tool to inhibit Wnt signaling in vivo. They will also provide new insight into understudied aspects of developmental biology, with connections to human disease, and establish a new Porcn/Wnt-focused research program in our lab. PUBLIC HEALTH RELEVANCE: Focal dermal hypoplasia (FDH) is a rare disease that affects the Wnt signaling pathway, which itself is very commonly dysregulated in additional congenital and acquired diseases. FDH is caused by mutations in the PORCN gene, for which we have generated a novel mouse genetic model. This proposal focuses on aspects of FDH that are also relevant to other diseases, and highlights the usefulness of mouse PORCN mutants to model disorders of Wnt signaling in humans.

描述（由申请人提供）：研究人员可以通过生物化学或正向遗传学来找出人类生理学和病理学的分子基础，或者它们可以以寻求治疗常见或罕见先天性疾病的患者的形式呈现。这些双重方法经常趋同，例如 X 连锁显性人类疾病局灶性真皮发育不全 (FDH) 的情况。这种综合征最近被定位到 PORCN 基因，该基因是果蝇豪猪基因的独特同源物，是分泌 Wnt 配体所需的。尽管 Wnt 被认为调节发育和疾病的许多方面，但哺乳动物配体功能的遗传学研究由于 19 个家族成员之间的冗余而变得复杂。为了建立克服这种冗余的遗传工具，我们的实验室产生了小鼠 Porcn 的条件敲除等位基因，并证明它提供了 FDH 的动物模型。基于我们最近发表的研究结果，我们在此建议检查与 FDH、异位脂肪沉积和不完全体壁闭合相关的两种新颖且与疾病相关的表型，我们的小鼠模型提供了独特的途径。我们的初步研究结果表明，这些表型具有共同的外胚层病因，我们将在三个具体目标中进行研究：（1）确定外胚层表达的 Wnt 蛋白生产中对 Porcn 的需求； (2) 表征 Porcn 介导的 Wnt 信号在抑制脂肪生成中的作用； (3)分析Porcn突变小鼠作为体壁闭合缺陷模型。这些研究将牢固确立 Porcn 突变体作为 FDH 模型和作为抑制体内 Wnt 信号传导的工具的实用性。他们还将为发育生物学的未充分研究的方面提供新的见解，以及与人类疾病的联系，并在我们的实验室建立一个新的以 Porcn/Wnt 为重点的研究项目。公共健康相关性：局灶性真皮发育不全 (FDH) 是一种影响 Wnt 信号通路的罕见疾病，该通路本身在其他先天性和获得性疾病中通常失调。 FDH 是由 PORCN 基因突变引起的，我们为此构建了一种新型小鼠遗传模型。该提案重点关注 FDH 与其他疾病相关的方面，并强调小鼠 PORCN 突变体在模拟人类 Wnt 信号传导疾病方面的有用性。