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Mechanistic characterizations of redox regulations and functions of Arf and Rho families

Arf 和 Rho 家族氧化还原调节和功能的机制表征

基本信息

批准号：
10796624
负责人：
Jongyun Heo
金额：
$ 44.92万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10796624
关键词：
Binding Biochemical Biochemistry Biological Assay Cardiovascular Diseases Cell physiology Cells Cellular biology Characteristics Classification Communities Complex Complication Development Disease Dissociation Drug Controls Education Event Family GTP Binding Goals Grant Guanine Nucleotide Dissociation Inhibitors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Immune Immune System Diseases Invaded Investigation Kinetics Knowledge Link Literature Mechanics Membrane Protein Traffic Methods Molecular Monomeric GTP-Binding Proteins Motivation Mutagenesis Nucleotides Oxidation-Reduction Pharmaceutical Preparations Play Property Protein Family Proteins Regulation Research Research Personnel Respiratory Burst Role Running Signal Transduction Specific qualifier value Superoxides Therapeutic Therapeutic Intervention Vacuum analog analytical method base desensitization graduate student innovation insight interdisciplinary approach novel novel therapeutic intervention nucleotide analog protein function response rho rho GTP-Binding Proteins therapeutically effective therapy development undergraduate student

项目摘要

Project Summary: Small GTPases play critical roles in cellular functions. They can be classified into several groups, including the Arf, Rab, Ras, Rho, and Ran families of proteins. The redox regulations and functions of the Arf families of small GTPases are unknown. The redox regulations and functions of the Rho families of small GTPases are only partly known. Without knowing them, the development of effective therapeutics for diseases associated with them is impractical. One long-term objective of this project is to understand the redox-dependent regulations and functions of these proteins. Another objective is to develop therapeutic interventions for these diseases. This objective includes the identification of the novel redox inert nucleotides that seem to target the redox- sensitive Arf and Rho proteins to block their redox responses. To achieve these goals, the previously unknown redox-sensitive motifs found in the Arf families of proteins will be characterized by using a multidisciplinary approach that includes mutagenesis-based redox biochemistry with novel mechanism-based nucleotide analogs as well as mass spectrometric, EPR spectroscopic, and cell biology methods. The multidisciplinary approach will also be used to refine and characterize previously unknown redox-sensitive motifs found in Rho proteins. The characterizations gained by using mutagenesis-based redox biochemistry and cell biology as well as other analytical methods will identify the unprecedented regulatory features and redox response properties of the new and refined redox-sensitive motifs found in Arf and Rho GTPases. The feature characteristics of these redox motifs in these proteins will then be classified based on their novel redox response properties. These classifications will further allow a systematic mechanistic investigation of the detailed redox control and action of these redox motifs in these small GTPases. This systematic mechanistic study will then specify the regulations of and mechanisms of the actions of the new and refined redox-sensitive motifs found in the Arf and Rho families of small GTPases. Furthermore, the redox biochemical analysis of this multidisciplinary approach includes the use of nucleotide analogs that are novel redox-inert nucleotides. The use of these analogs is not only to inspect the mechanisms of the actions of these redox motifs in the small GTPases but also to provide insight into a novel therapeutic strategy in which a redox desensitization of these motifs alleviates or terminates diseases associated with the unchecked redox response of these motifs in the small GTPases.

项目概要：小 GTP 酶在细胞功能中发挥着关键作用。它们可以分为几组，包括 Arf、Rab、Ras、Rho 和 Ran 蛋白质家族。 Arf家族的氧化还原调控和功能小 GTP 酶未知。小 GTPase 的 Rho 家族的氧化还原调节和功能仅部分已知。在不了解它们的情况下，开发出针对与以下疾病相关的疾病的有效疗法：它们是不切实际的。该项目的长期目标之一是了解氧化还原相关的法规以及这些蛋白质的功能。另一个目标是开发针对这些疾病的治疗干预措施。该目标包括鉴定新型氧化还原惰性核苷酸，这些核苷酸似乎靶向氧化还原- 敏感的 Arf 和 Rho 蛋白可阻止其氧化还原反应。为了实现这些目标，在 Arf 蛋白质家族中发现了以前未知的氧化还原敏感基序其特点是使用多学科方法，包括基于诱变的氧化还原基于新机制的核苷酸类似物的生物化学以及质谱、EPR 光谱和细胞生物学方法。多学科方法也将用于完善和表征了 Rho 蛋白中以前未知的氧化还原敏感基序。获得的特征使用基于诱变的氧化还原生物化学和细胞生物学以及其他分析方法将识别新型和精致的氧化还原敏感的前所未有的调节特征和氧化还原响应特性 Arf 和 Rho GTPases 中发现的基序。这些蛋白质中这些氧化还原基序的特征将然后根据其新颖的氧化还原响应特性进行分类。这些分类将进一步允许对这些氧化还原基序的详细氧化还原控制和作用进行系统的机制研究小GTPa酶。这项系统的机制研究将明确具体的规则和机制。小 GTPase 的 Arf 和 Rho 家族中发现的新的和精致的氧化还原敏感基序的作用。此外，这种多学科方法的氧化还原生化分析包括使用核苷酸新型氧化还原惰性核苷酸的类似物。使用这些类似物不仅是为了检查机制这些氧化还原基序在小 GTP 酶中的作用，同时也提供了对新型治疗方法的见解策略，其中这些基序的氧化还原脱敏减轻或终止与这些基序在小 GTP 酶中不受控制的氧化还原反应。