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Imaging Protein Tyrosine Phosphorylation in vivo

体内蛋白质酪氨酸磷酸化成像

基本信息

批准号：
7184604
负责人：
AMY M BARRIOS
金额：
$ 20.74万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7184604
关键词：
Amino Acids Autoimmune Diseases Autoimmunity Biochemistry Biological Biological Assay Biological Models Biological Process Cell Line Cell physiology Cells Cellular biology Chemicals Condition D Cells Development Diabetes Mellitus Disease Enzymes Equilibrium Exploratory/Developmental Grant Family Fluorescent Probes Funding Future Health Hypersensitivity Image Imaging Techniques Immune System Diseases Immunologic Deficiency Syndromes In Vitro Individual Investigation Kinetics Knowledge Learning Life Malignant Neoplasms Mammalian Cell Methodology Methods Minor Numbers Peptides Phosphoric Monoester Hydrolases Phosphorylation Physiological Principal Investigator Process Protein Dephosphorylation Protein Overexpression Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Receptor Signaling Reporting Research Research Personnel Research Project Grants Role Role playing therapy Series Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Stimulus Synthesis Chemistry T-Cell Receptor T-Lymphocyte Techniques Time Tyrosine Tyrosine Phosphorylation analog antigen binding base computerized data processing design enzyme activity human disease improved in vivo interest new technology novel novel therapeutics response therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The phosphorylation and dephosphorylation of tyrosine residues in proteins and enzymes is crucial to many cellular signaling pathways in both health and disease. In vivo, tyrosine phosphorylation is dynamic and tightly controlled by the concerted actions of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs). Although the importance of tyrosine phosphorylation has been recognized for many years, the tools necessary to probe the phosphorylation and dephosphorylation of key tyrosine residues in important signaling proteins have been slow to develop. In this exploratory/developmental research project, we will create a new set of chemical probes of tyrosine phosphorylation. These probes will be incorporated into living cells and used to image tyrosine phosphorylation and dephosphorylation in vivo. The long-term objectives of this project are to establish a novel technology for real-time analysis of tyrosine phosphorylation in vivo and demonstrate its utility in the investigation of cell signaling under physiological and pathological conditions. To this end, we present the following SPECIFIC AIMS: (1) Develop and validate a series of novel peptide-based probes for PTP/PTK activity in vitro, (2) Illustrate the utility of these novel probes in imaging dynamic tyrosine phosphorylation/dephosphorylation processes in vivo. The research described in this proposal requires the unique combination of expertise in synthetic chemistry, biochemistry and cell biology embodied by the two Principal Investigators. Funding for this developmental project through the EBRG R21 mechanism will be instrumental in validating the new technology for imaging tyrosine phosphorylation and paving the way for future hypothesis-driven research on the importance of tyrosine phosphorylation in cellular signaling processes. RELEVANCE: Both tyrosine phosphatase and tyrosine kinase enzymes are important therapeutic targets for the treatment of many human diseases including diabetes, autoimmune disorders and cancer. In this research project we will develop a new technique for investigating the activity of these enzymes in live cells and in real time. This technique will help us to learn more about these enzymes in both health and disease, and ultimately facilitate the design of novel therapeutics.

描述（由申请人提供）：蛋白质和酶中酪氨酸残基的磷酸化和去磷酸化对于健康和疾病中的许多细胞信号传导途径至关重要。在体内，酪氨酸磷酸化是动态的，并受到蛋白酪氨酸磷酸酶（PTP）和蛋白酪氨酸激酶（PTK）的协同作用的严格控制。尽管多年来人们已经认识到酪氨酸磷酸化的重要性，但探测重要信号蛋白中关键酪氨酸残基的磷酸化和去磷酸化所需的工具的开发进展缓慢。在这个探索性/开发性研究项目中，我们将创建一套新的酪氨酸磷酸化化学探针。这些探针将被整合到活细胞中并用于体内酪氨酸磷酸化和去磷酸化的成像。该项目的长期目标是建立一种实时分析体内酪氨酸磷酸化的新技术，并证明其在生理和病理条件下细胞信号传导研究中的实用性。为此，我们提出以下具体目标：（1）开发并验证一系列新型基于肽的探针，用于体外 PTP/PTK 活性，（2）说明这些新型探针在体内动态酪氨酸磷酸化/去磷酸化过程成像中的实用性。该提案中描述的研究需要两位首席研究员在合成化学、生物化学和细胞生物学方面的专业知识的独特结合。通过 EBRG R21 机制资助这一开发项目将有助于验证酪氨酸磷酸化成像新技术，并为未来关于酪氨酸磷酸化在细胞信号传导过程中的重要性的假设驱动研究铺平道路。相关性：酪氨酸磷酸酶和酪氨酸激酶都是治疗许多人类疾病（包括糖尿病、自身免疫性疾病和癌症）的重要治疗靶点。在这个研究项目中，我们将开发一种新技术来实时研究这些酶在活细胞中的活性。这项技术将帮助我们更多地了解这些酶在健康和疾病中的作用，并最终促进新型疗法的设计。