Fibulin-1 Regulation of the DiGeorge Syndrome Pathogenesis Pathway

Fibulin-1 对 DiGeorge 综合征发病机制的调节

基本信息

批准号：
7994829
负责人：
WILLIAM SCOTT ARGRAVES
金额：
$ 36.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994829
关键词：
22q11 Affect Apoptosis Area Birth Boxing Branchial arch structure Cardiac Cell Proliferation Cell physiology Cells Cephalic Congenital Abnormality Congenital Heart Defects Cranial Nerves DNA Microarray Chip Development DiGeorge Syndrome Embryo Etiology Exhibits Extracellular Matrix Proteins Frequencies Gene Silencing Genetic Gland Glossopharyngeal nerve structure Growth Factor Heart Human Immigration Lead Maps Mediating Mesenchyme Microarray Analysis Molecular Mus Myocardium Neural Crest Cell Neural tube Parathyroid gland Pathogenesis Pathway interactions Pattern Phenotype Phosphotransferases Play Primordium Proteoglycan Proteolysis Pulmonary artery structure Regulation Research Research Design Role Signal Pathway Somites Structure Testing Thymus Gland Thyroid Gland Tissues Ventricular bone cell behavior cell motility craniofacial cranium fibulin 1 hindbrain insight malformation migration novel public health relevance stem transcription factor versican

项目摘要

DESCRIPTION (provided by applicant): New findings from targeted gene inactivation studies in mice reveal that the extracellular matrix protein fibulin-1 (Fbln1) is required for normal development of the cardiac outflow tract (OFT), pharyngeal glands, cranial nerves and bones of the skull. The developmental anomalies displayed by mice deficient in Fbln1 recapitulate many of the anomalies associated with 22q11 deletion/DiGeorge syndrome (DGS), which occurs with a frequency of 1:4000 human births. The similarity in phenotypes between Fbln1-deficient mice and DGS humans suggests that Fbln1, although located outside of the 22q11 deletion region, is a modifier of the pathway that is dysfunctional in DGS. The molecular pathway of DGS has not been fully elucidated. Key components are the transcription factor Tbx1, Fgf8 and intermediates of the Fgf8 signaling pathway. Several lines of evidence support the hypothesis that Fbln1 regulates this pathway. DNA microarray analysis indicates that Fbln1 is required for expression of forkhead box transcription factors that regulate expression of both Tbx1 and Fgf8 in pharyngeal arch regions including the secondary heart field (SHF). qPCR analysis shows that Tbx1 expression is significantly decreased in pharyngeal arch-containing tissues from Fbln1 null embryos. We also find that Fbln1 interacts with Fgf8 and inhibits Fgf8-mediated activation of the Map kinase-signaling pathway. These observations together with findings that Fbln1 is expressed along pathways of NCC migration, that it can act as a regulator of cell guidance and motility and that it interacts and modulates proteolysis of the proteoglycan versican, a regulator of NCC migration, lead to the following hypothesis: Fbln1 is a key component of the mechanism by which Fgf8 influences NCC-dependent development of the pharyngeal arch and the formation of derivative structures including the OFT, pharyngeal glands and craniofacial structures. To test this hypothesis and gain mechanistic understanding there are three specific aims: 1) Define the effects of Fbln1 on the Fgf8 signaling pathway; 2) Identify genetic interactions between Fbln1 and Tbx1 and between Fbln1 and versican; and 3) Define the role of Fbln1 in controlling NCC proliferation and guidance. Findings from this experimentation are expected to lead to new insights into the mechanism by which Fbln1 guides the normal development of the cardiac OFT, great vessels, cranium and pharyngeal glands and to contribute to an understanding of the etiology of congenital defects involving these tissues. Public Health Relevance: This research seeks to gain a mechanistic understanding of the developmental anomalies (including heart defects) associated with DiGeorge syndrome (DGS), which occurs with a frequency of one in 4000 human births. The proposed studies are designed to determine the role of the extracellular matrix protein, fibulin-1, in regulating the behaviors of cells (neural crest cells) that contribute to the formation of tissues affected in DGS. A novel direction for the research stems from our discovery that fibulin-1 regulates the activity of Fgf8, a growth factor implicated as a key component of the pathway that is dysfunctional in DGS.

描述（由申请人提供）：小鼠靶向基因失活研究的新发现表明，细胞外基质蛋白纤维蛋白-1（FBLN1）对于心脏流出道（OFT），咽腺，颅神经，颅神经和颅骨的正常发展是必需的。缺乏FBLN1的小鼠所显示的发育异常概括了与22q11删除/Digeorge综合征（DGS）相关的许多异常，该异常的发生频率为1：4000人类。 FBLN1缺陷型小鼠和DGS人类之间表型的相似性表明，尽管FBLN1位于22Q11缺失区域之外，但是DGS功能失调的途径的修饰符。 DGS的分子途径尚未完全阐明。关键成分是FGF8信号通路的转录因子TBX1，FGF8和中间体。几条证据支持FBLN1调节这一途径的假设。 DNA微阵列分析表明，FBLN1是表达叉头盒转录因子所必需的，这些转录因子在包括次级心脏场（SHF）在内的咽弓区域调节TBX1和FGF8的表达。 QPCR分析表明，来自FBLN1无效胚胎的咽弓形组织中TBX1的表达显着降低。我们还发现FBLN1与FGF8相互作用，并抑制FGF8介导的MAP激酶信号途径的激活。 These observations together with findings that Fbln1 is expressed along pathways of NCC migration, that it can act as a regulator of cell guidance and motility and that it interacts and modulates proteolysis of the proteoglycan versican, a regulator of NCC migration, lead to the following hypothesis: Fbln1 is a key component of the mechanism by which Fgf8 influences NCC-dependent development of the pharyngeal arch以及包括OFT，咽腺和颅面结构在内的衍生结构的形成。为了检验这一假设并获得机械理解，有三个特定的目的：1）定义FBLN1对FGF8信号通路的影响； 2）确定FBLN1和TBX1之间以及FBLN1和Versican之间的遗传相互作用； 3）定义FBLN1在控制NCC增殖和指导中的作用。预计该实验的结果将导致对FBLN1指导心脏OFT，大血管，颅骨和咽腺正常发育的机制的新见解，并有助于理解涉及这些组织的先天性缺陷的病因。公共卫生相关性：这项研究试图对与Digeorge综合征（DGS）相关的发育异常（包括心脏缺陷）获得机械理解，该综合症（DGS）的发生频率为4000个人类出生。拟议的研究旨在确定细胞外基质蛋白Fibulin-1在调节导致DGS中影响组织形成的细胞（神经rest细胞）行为中的作用。这项研究的新方向源于我们的发现，即菲堡-1调节FGF8的活性，FGF8的活性是DGS中功能失调的途径的关键组成部分。