Regulating TGF-beta Signaling in Drosophila

调节果蝇中的 TGF-β 信号传导

• 批准号: 8464159
• 负责人: MICHAEL Brendan O'CONNOR
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/8464159
• 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

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（申请人提供）：TGF-β超家族是人类中发现的最大的一类分泌型信号分子，它们调节大量的细胞、发育和生理过程，包括早期轴向发育、胚层特化、原肠胚形成、器官发生和左右不对称。我们将使用一个经过充分研究的模式生物（果蝇）来阐明在发育过程中调节TGF-β信号通路活动的一般原则。在目标1中，我们将研究三种新的基因产物在早期胚胎中控制Dpp信号传导的机制。这些实验将显著提高我们对细胞外因子如何影响体内TGF-β因子的信号传导动力学的理解。在目标2中，我们将使用果蝇分子遗传学和蛋白质组学在MDCK细胞中的组合来确定TGF-β II型受体在上皮细胞中基底外侧定位的功能意义和机制。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被递送到细胞膜的不同亚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，以确定一个亚家族（激活素）如何影响另一个亚家族（骨形成蛋白）的信号输出，以控制组织生长。这项工作将确定跨TGF-β通路信号传导或非经典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因子的表达或调节的遗传和体细胞突变是许多疾病过程的主要贡献者，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旨在治疗各种疾病或损伤情况期间操纵该途径的活性的治疗干预策略。我们的研究旨在了解这些因子的活性是如何在时间和空间上在模式生物中进行调节的，这有助于确定新的治疗靶点和/或开发或更有效的治疗方案。