Regulating TGF-beta Signaling in Drosophila

调节果蝇中的 TGF-β 信号传导

基本信息

批准号：
8316134
负责人：
MICHAEL Brendan O'CONNOR
金额：
$ 32.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316134
关键词：
Activins Affect Animal Model Animals Anterior Apical Apoptosis Binding Proteins Biochemical Biological Cardiovascular Diseases Cell Proliferation Cell membrane Cell physiology Cells Cleaved cell Clinic Collaborations Communities Complex Computer Simulation Connective Tissue Diseases Development Developmental Process Disease Dorsal Drosophila genus Embryo Embryonic Development Epithelial Cells Epithelium Family Fibrosis Gene Mutation Genetic Germ Layers Growth Growth Inhibitors Health Heart Diseases Human Human Genetics Human Pathology Immune Immune system Injury Intervention Knowledge Lateral Left Ligands MDCK cell Malignant Neoplasms Mediating Mediator of activation protein Medical Membrane Metalloproteases Methods Molecular Molecular Genetics Names Neoplasm Metastasis Organogenesis Output Pathway interactions Pattern Physiological Processes Play Process Proteins Proteomics Recycling Regulation Repression Role Shrews Signal Pathway Signal Transduction Signaling Molecule Societies Somatic Mutation Stem cells Study models Surface System Therapeutic Intervention Time Tissues Transforming Growth Factor beta Transport Process Treatment Protocols Type I Activin Receptors Wing Wit Work Wound Healing base basolateral membrane bone morphogenetic protein receptor type II effective therapy extracellular gastrulation gene function human disease imaginal disc improved in vivo insight man member new therapeutic target novel novel therapeutics polypeptide receptor research study trafficking tumor progression

项目摘要

DESCRIPTION (provided by applicant): The TGF-ss superfamily is the largest group of secreted signaling molecules found in man. They regulate a very large number of cellular, developmental and physiological processes including early axial development, germ layer specification, gastrulation, organogenesis, and left right asymmetry. We will use a well-studied model organism (Drosophila) to elucidate general principles by which the activities of TGF-ss signaling pathways are regulated during development. In Aim 1 we will examine mechanisms by which three new gene products control Dpp signaling in the early embryo. These experiments will significantly improve our understanding of how extracellular factors, affect signaling dynamics of TGF-ss factors in vivo. In Aim 2 we will determine the functional significance and mechanism of TGF-ss type II receptor basolateral localization in epithelial cells using a combination of Drosophila molecular genetics and proteomics in MDCK cells. These experiments will considerably enhance our understanding of how receptors in this major signaling pathway are delivered to different sub-compartments of the cell membrane and how this affects tissue development. In Aim 3 we will use molecular genetics methods, to determine how one sub-family (Activins) influences the signaling output of another subfamily (BMPs) to control tissue growth. This work will determine whether cross TGF-ss- pathway signaling or non-canonical signaling contributes to growth regulation, an important issue in the development of many tissues and disease processes. Impact on human health: In humans, genetic and somatic mutations that alter the expression or regulation of TGF-ss factors are major contributors to numerous disease processes including cancer, metastasis, fibrosis, immune regulation, cardiovascular disease, and connective tissue disorders. Therefore, there is currently much effort within the medical community to develop therapeutic intervention strategies aimed at manipulating the activities of this pathway during treatment of various disease or injury situations. Our studies aimed at understanding how the activity of these factors is regulated in time and space in a model organism should aid in the identification of new therapeutic targets and/or development or more effective treatment protocols.

描述（由申请人提供）：TGF-β超家族是人类中发现的最大的分泌信号分子群。它们调节大量的细胞、发育和生理过程，包括早期轴向发育、胚层规范、原肠胚形成、器官发生和左右不对称。我们将使用经过充分研究的模型生物（果蝇）来阐明发育过程中调节 TGF-β 信号通路活性的一般原理。在目标 1 中，我们将研究三种新基因产物控制早期胚胎中 Dpp 信号传导的机制。这些实验将显着提高我们对细胞外因子如何影响体内 TGF-β 因子信号动力学的理解。在目标 2 中，我们将结合果蝇分子遗传学和 MDCK 细胞中的蛋白质组学来确定 TGF-β II 型受体基底外侧定位在上皮细胞中的功能意义和机制。这些实验将大大增强我们对这一主要信号通路中的受体如何传递到细胞膜的不同子区室以及这如何影响组织发育的理解。在目标 3 中，我们将使用分子遗传学方法来确定一个亚家族（激活素）如何影响另一个亚家族（BMP）的信号输出以控制组织生长。这项工作将确定跨 TGF-β 途径信号传导或非规范信号传导是否有助于生长调节，这是许多组织和疾病过程发展中的一个重要问题。对人类健康的影响：在人类中，改变 TGF-β 因子表达或调节的基因和体细胞突变是许多疾病过程的主要原因，包括癌症、转移、纤维化、免疫调节、心血管疾病和结缔组织疾病。因此，目前医学界正在努力开发治疗干预策略，旨在在治疗各种疾病或损伤情况期间操纵该途径的活动。我们的研究旨在了解这些因子的活性在模型生物体中如何在时间和空间上受到调节，这应有助于确定新的治疗靶点和/或开发或更有效的治疗方案。