Functional Analysis of Sprouty Genes in Limb Development

Sprouty 基因在肢体发育中的功能分析

基本信息

批准号：
7467928
负责人：
BENJAMIN DIUNG-YUEN YU
金额：
$ 12.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7467928
关键词：
Affect Animals Apical Ectodermal Ridge Biochemical Biochemical Pathway Biological Assay Branchial arch structure Cell Line Cell Survival Cells Complex Defect Development Digit structure Dissection Drosophila genus Drosophila melanogaster Embryo Embryonic Development Failure to Thrive Family Fibroblast Growth Factor Fibroblasts Functional disorder Gene Proteins Gene Silencing Genes Genetic Models Genetic Screening Genetic screening method Growth Growth Factor Homeostasis Human Inherited Kidney Knock-out Knowledge Laboratories Laboratory Study Limb Development Limb structure Lung Malignant Neoplasms Mammalian Cell Mediating Mesenchymal Mesoderm Molecular Morphogenesis Multiple Abnormalities Mus Names Neoplastic Cell Transformation Normal tissue morphology Numbers Pathway interactions Pattern Phenotype Pigmentation physiologic function Play Predisposition Process Protein Overexpression Range Regulation Research Personnel Role Signal Pathway Signal Transduction Signaling Molecule Site Skin Structure Technology Testing Thinking Time Ursidae Family Vertebrates Xenopus Zebrafish base bone dosage fibroblast growth factor 6 fibroblast growth factor receptor 4 hindbrain human disease in vivo inhibitor/antagonist insight malformation novel programs receptor research study response tumor progression

项目摘要

DESCRIPTION (provided by applicant): Growth factors and their receptors play a prominent role in inherited human diseases, which range from malformations of bone, vasculature, pigmentation, and digits to abnormalities which contribute to cancer predisposition. During embryonic development, growth factor signals must be precisely controlled in order for normal development to occur. Although growth factors are known to be important in contributing to cell survival and growth, it is not precisely known how they signals trigger and mediate extremely complex structures such as the limb, the lung, the kidney, and the skin. In addition to the normal regulatory controls of the cell to limit overactivity and duration of growth factor signals, other inhibitors of growth factor signaling may actually play a role themselves in direct growth and patterning of complex structures. Recently, a novel family of inhibitors was identified in Drosophila as an important contributor to the complex process of tracheal branching. The inhibitors were thus given the name, Sprouty. The Sprouty gene is evolutionarily conserved and in human, there are four Sprouty genes, Spry1, 2, 3, and 4. They are known to inhibit the growth factor, fibroblast growth factor (FGF), and may affect other growth factors as well. It is possible that Sprouty genes and the proteins they encode contribute to the patterning complex structures in vertebrates. Our laboratory studies the complex process of limb development and in particular the role that FGFs play in its patterning. The Sprouty genes are turned out in the limb at approximately the same time that FGFs are expressed. I hypothesize that Sprouty genes play a role in patterning the limb. To test this question, he has analyzed the effect of the loss of Spry4 on the development of the limb. Loss of Spry4 leads to a number of digit malformations, many of them resemble digit defects in humans. In this proposal, I will study the molecular basis for these abnormalities and determine the contribution of FGF signaling and other Sprouty genes in these digit defects. These studies will provide insights into how Spry4 affects FGF signaling and into how complex structures are normally patterned.

描述（由申请人提供）：生长因子及其受体在遗传性的人类疾病中起着重要的作用，从骨骼的畸形，脉管系统，色素沉着和数字畸形到有助于癌症易感性的异常。在胚胎发育过程中，必须精确控制生长因子信号，以使正常发育发生。尽管已知生长因子在有助于细胞的存活和生长方面很重要，但尚不清楚它们如何触发并介导极其复杂的结构，例如肢体，肺，肾脏和皮肤。除了细胞的正常调节控制以限制生长因子信号的过度活动和持续时间外，其他生长因子信号传导的抑制剂实际上可能在直接生长和复杂结构的直接生长和模式中发挥作用。最近，在果蝇中发现了一种新型的抑制剂家族，是气管分支复杂过程的重要因素。因此，抑制剂的名称发芽。发芽的基因在进化上是保守的，在人类中，有四个发芽的基因Spry1、2、3和4。已知它们抑制生长因子，成纤维细胞生长因子（FGF），并可能影响其他生长因子。它们的发芽基因及其编码的蛋白质可能有助于脊椎动物中的图案复杂结构。我们的实验室研究肢体发育的复杂过程，尤其是FGF在其图案中所扮演的角色。大约在表达FGF的同一时间，发芽的基因被发现在肢体中。我假设发芽的基因在对肢体构图中起作用。为了测试这个问题，他分析了SPRY4损失对肢体发展的影响。 SPRY4的损失导致许多数字畸形，其中许多类似于人类的数字缺陷。在此提案中，我将研究这些异常的分子基础，并确定FGF信号传导和其他发芽基因在这些数字缺陷中的贡献。这些研究将提供有关SPRY4如何影响FGF信号传导以及对复杂结构通常具有图案方式的见解。