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Regulation of developmental signaling by beta-arrestin

β-抑制蛋白对发育信号的调节

基本信息

批准号：
8100601
负责人：
Alexey Veraksa
金额：
$ 29.04万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
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：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8100601
关键词：
Accounting Asthma Attention Biochemical Biological Biological Assay Biological Models Cell Communication Cells Data Development Diabetes Mellitus Disease Drosophila genus Drosophila melanogaster Embryo Embryonic Development Endocytosis Environment G-Protein-Coupled Receptors Genes Genetic Genetic Epistasis Germ-Line Mutation Goals Grant Health Heart Diseases Image Knowledge MAP Kinase Gene Malignant Neoplasms Measurement Mental Depression Methods Organism Pathway interactions Pattern Plant Roots Positioning Attribute Protein Isoforms Proteins Proteomics Receptor Protein-Tyrosine Kinases Regulation Relative (related person)Research Role Schizophrenia Screening procedure Signal Pathway Signal Transduction Students System Testing To specify Transgenic Organisms beta-arrestin clinically relevant desensitization design fly human disease in vivo innovation mRNA Expression notch protein novel prevent programs protein expression protein purification research study scaffold therapeutic target upstream kinase

项目摘要

The long term goal of the proposed research is to investigate the mechanisms that control cell communication during metazoan development. beta-arrestin proteins have recently emerged as multifunctional regulators of several signaling systems. beta-arrestins control signaling networks by associating with specific signaling components and modulating the duration, amplification, and routing of signals inside the cells. Because of their central position in signaling networks, beta-arrestins have been implicated in multiple human diseases, such as schizophrenia, depression, cancer, heart disease, asthma, and diabetes. Despite a large body of work on the signaling activities of beta-arrestins, their biological role in organism development is poorly understood. The goal of the current proposal is to investigate how a single beta-arrestin in Drosophila, Kurtz (Krz), controls two important developmental signaling networks. Preliminary data obtained in Drosophila embryos lacking krz suggest that the Krz protein inhibits the function of two signaling pathways that are active in early development: the receptor tyrosine kinase Torso/MAPK and Toll/NF-κB. Both of these pathways have clinical relevance in several human diseases such as cancer and immunological disorders. Drosophila offers a unique advantage as a genetically tractable and quantifiable system to dissect the role of beta-arrestin Krz in these pathways. Two specific aims will be pursued: 1) To study the role of interactions between Krz and MAPK ERK in the regulation of receptor tyrosine kinase signaling. The main objective of this aim is to identify regions in the Krz protein responsible for its interaction with ERK in a biochemical screening procedure, and to test the functional importance of these regions in receptor tyrosine kinase regulation using in vivo functional assays. An innovative quantitative imaging approach will be used to determine the relative importance of the identified Krz-ERK contact regions for the observed inhibitory effects of Krz on MAPK signaling. 2) To study the mechanisms of NF-κB regulation by Krz. A combination of genetics and novel proteomics strategies will be used to determine the likely mode of regulation of Toll signaling by Krz. The overall strength of the proposed research lies in an integration of genetics, proteomics, and quantitative measurements of mRNA and protein expression patterns. Such a multi-level approach, which is firmly rooted in functional in vivo studies, will likely advance our knowledge of the mechanisms used by beta-arrestins to control developmental signaling pathways, and may suggest new avenues for designing beta-arrestin-directed therapies.

拟议研究的长期目标是研究后生动物发育过程中控制细胞通讯的机制。 β-抑制蛋白最近已成为多种信号系统的多功能调节剂。 β-抑制蛋白通过与特定信号成分结合并调节细胞内信号的持续时间、放大和路由来控制信号网络。由于β-抑制蛋白在信号网络中的核心地位，它们与多种人类疾病有关，例如精神分裂症、抑郁症、癌症、心脏病、哮喘和糖尿病。尽管对β-抑制蛋白的信号活性进行了大量研究，但它们在生物体发育中的生物学作用仍知之甚少。当前提案的目标是研究果蝇中的单个 β-抑制蛋白 Kurtz (Krz) 如何控制两个重要的发育信号网络。在缺乏 krz 的果蝇胚胎中获得的初步数据表明，Krz 蛋白抑制早期发育中活跃的两条信号通路的功能：受体酪氨酸激酶 Torso/MAPK 和 Toll/NF-κB。这两种途径在癌症和免疫性疾病等多种人类疾病中都具有临床意义。果蝇作为遗传上易于处理和量化的系统，具有独特的优势，可以剖析 β-arrestin Krz 在这些途径中的作用。我们将追求两个具体目标：1) 研究 Krz 和 MAPK ERK 之间的相互作用在受体酪氨酸激酶信号传导调节中的作用。该目的的主要目的是在生化筛选过程中鉴定 Krz 蛋白中负责与 ERK 相互作用的区域，并使用体内功能测定来测试这些区域在受体酪氨酸激酶调节中的功能重要性。将使用创新的定量成像方法来确定已识别的 Krz-ERK 接触区域对于观察到的 Krz 对 MAPK 信号传导的抑制作用的相对重要性。 2)研究Krz对NF-κB的调控机制。遗传学和新型蛋白质组学策略的结合将用于确定 Krz 对 Toll 信号传导的可能调节模式。拟议研究的整体优势在于遗传学、蛋白质组学以及 mRNA 和蛋白质表达模式的定量测量的整合。这种牢固植根于功能性体内研究的多层次方法可能会增进我们对β-抑制蛋白控制发育信号通路机制的了解，并可能为设计β-抑制蛋白导向疗法提供新途径。