Chemistry and Biology of ADP-Ribosylation-Dependent Signaling

ADP 核糖基化依赖性信号传导的化学和生物学

• 批准号: 10026899
• 负责人: Yong Zhang
• 金额: $ 39.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10026899
• 关键词: ADP Ribose Transferases; ADP ribosylation; Address; Adenosine Diphosphate Ribose; Area; Biological Process; Biology; Cell physiology; Chemicals; Chemistry; Complex; Development; Disease; Dissection; Event; Functional disorder; Goals; Health; Human; Individual; Lead; Mediating; Nicotinamide adenine dinucleotide; Pathogenesis; Pathway interactions; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Proteins; Reader; Research; Role; Signal Transduction; Technology; Work; human disease; innovation; new therapeutic target; novel; novel diagnostics; tool

Abstract Protein ADP-ribosylation is a complex and highly dynamic process regulated by distinct writer, reader and eraser proteins. As a key post-translational modification, protein ADP-ribosylation is catalyzed by ADP- ribosyltransferases (ARTs) by using nicotinamide adenine dinucleotide (NAD+) as a co-substrate and plays important roles in regulating a significant number of physiological and pathophysiological processes. ADP- ribosylated proteins can be recognized by reader proteins, triggering downstream signaling cascades or effector functions in direct or indirect manners. The ADP-ribosylation-mediated signaling can be modulated by eraser proteins that rapidly remove covalently attached ADP-ribose unit(s). In addition to their extensive involvements in physiological events, the writers, readers, and erasers of protein ADP-ribosylation are broadly implicated in numerous diseases. However, it remains elusive for the functions and roles of ADP-ribosylation in human health and pathogenesis of many diseases. Despite technological advancement, little information is known regarding the identity of the reader(s) and eraser(s) for individual ADP-ribosylated proteins, the preferred ADP-ribosylated protein(s) for a specific reader or eraser protein, and the ADP-ribosylation-centered interaction networks. And tools and technologies have yet to be developed for unambiguously mapping ADP-ribosylation-dependent interactome. The goal of this MIRA project is to develop novel chemical tools to address these major challenges. In next five years, we are aimed to generate novel bifunctional NAD+ molecules for unbiased and faithful dissection of ADP-ribosylation-dependent interactome and define their roles in cell signaling. Successful completion of this work will result in a set of novel and important chemical tools for addressing challenges in research on ADP-ribosylation-dependent events and processes across multiple areas. These innovative tools may lead to major breakthroughs in understanding of the cellular functions and regulatory roles of protein ADP- ribosylation in physiology and pathophysiology and in the development of novel diagnostics and therapeutics targeting ADP-ribosylation-associated activities and pathways for many human diseases.

抽象的 蛋白质ADP-核糖基化是一个复杂且高度动态的过程，由不同的作者，读者和 橡皮蛋白。作为关键的翻译后修饰，蛋白ADP-核糖基化被ADP-催化 核糖基转移酶（Arts）使用烟酰胺腺苷二核苷酸（NAD+）作为共覆盖物并玩耍 在调节大量生理和病理生理过程中的重要作用。 adp- 核糖基化蛋白可以通过读取器蛋白识别，从而触发下游信号级联反应或效应器 以直接或间接的方式发挥作用。 ADP-核糖基化介导的信号可以通过橡皮擦调节 迅速去除共价附着的ADP-核糖单元的蛋白质。除了他们的广泛参与 在生理事件中，蛋白质ADP-核糖基化的作家，读者和橡皮擦广泛涉及 许多疾病。但是，对于ADP-核糖化在人类健康中的功能和作用仍然难以捉摸 和许多疾病的发病机理。尽管技术进步，但知之甚少 对于单个ADP-核糖基化蛋白的读取器和橡皮擦的身份，首选的ADP-核糖基化 特定读取器或橡皮擦蛋白的蛋白质，以及以ADP-核糖基化相互作用网络的蛋白质。和 工具和技术尚未开发用于明确映射ADP-核糖基化依赖性的 Interactome。这个MIRA项目的目标是开发新型的化学工具来应对这些主要挑战。 在接下来的五年中，我们的目的是为无偏见和忠实的新颖的双功能NAD+分子 ADP-核糖基化依赖性相互作用组的解剖，并定义其在细胞信号传导中的作用。成功的 这项工作的完成将导致一系列新颖而重要的化学工具来应对挑战 研究多个领域的ADP-核糖基化依赖性事件和过程。这些创新的工具 在理解蛋白ADP的细胞功能和调节作用方面可能会带来重大突破 生理学和病理生理学的核糖基化以及新型诊断和治疗学的发展 靶向许多人类疾病的ADP-核糖基化相关活性和途径。