Regulation of the cell proliferation by CRL ubiquitin ligases

CRL 泛素连接酶对细胞增殖的调节

• 批准号: 10590637
• 负责人: MICHELE PAGANO
• 金额: $ 33.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590637
• 关键词: Area; Autophagocytosis; Biochemical; Biological; Biological Process; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation Regulation; Cell physiology; Cells; Clinical; Communicable Diseases; Complex; Cullin Proteins; DNA Damage; DNA Repair; Dimensions; Enzymes; Etiology; Genetic; Goals; Laboratories; Life; Light; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Metabolic Diseases; Molecular; Neurodegenerative Disorders; New Territories; Oncology; Play; Process; Proliferating; Proteomics; Regulation; Research; Role; Signal Transduction; Signal Transduction Pathway; Sleep Disorders; System; Thalidomide; Ubiquitin; circadian pacemaker; field study; human disease; immune modulating agents; in vivo; insight; interdisciplinary approach; interest; multicatalytic endopeptidase complex; novel therapeutic intervention; response; success; ubiquitin ligase

PROJECT ABSTRACT / SUMMARY More than 30 years have passed since the discovery of the ubiquitin-proteasome system, yet we still lack comprehensive insights into its regulatory mechanisms. This limitation arises because most of the approximately 600 ubiquitin ligase enzymes in mammals remain largely uncharacterized. Our laboratory has focused on how Cullin-RING Ubiquitin Ligase (CRL) complexes control the three essential dimensions of cellular life: proliferation, survival, and differentiation. We have played a central role in elucidating how, when, where and, most importantly, why CRLs mediate the degradation of key cellular regulators. The research in my laboratory initially focused on the paradigm of the timed regulation of the mammalian cell cycle by the ubiquitin-proteasome system, which we established a number of years ago. We have since expanded our research into five fields of study: (i) cell signaling, (ii) cell cycle control, (iii) the DNA damage response, (iv) oncology, and (v) the circadian clock. This expansion of our interests has been possible thanks to our discovery-driven approach that, in contrast to the more common hypothesis-driven approach, is unbiased. Yet, the results of genetics and proteomics screens are not our end goal, but they guide us to explain the underlying biological concepts and mechanisms. Importantly, they often lead us to unexpected and unexplored new territories, opening our horizons. In summary, we use a comprehensive and interdisciplinary approach to break new grounds and make transformative discoveries that will provide new mechanistic insights into fundamental biological processes, particularly those processes that are regulated by CRLs. The current proposed research will cover all the mechanistic studies performed in our laboratory concerning areas i-iii listed above. In particular, we will leverage our recognized expertise in the ubiquitin field to discover molecular mechanisms by which CRLs control signal transduction pathways, autophagy, cell cycle progression, and DNA repair. Moreover, we will perform biochemical, cellular and in vivo analyses to illuminate how CRLs are regulated to function as switches between diverse cell fates. These findings will substantially advance our understanding of the proper execution of crucial cellular processes, potentially shedding light on the etiologies and treatments of human diseases.

项目摘要/摘要 自发现泛素-蛋白酶体系统以来，已经过去了30多年 我们仍然缺乏对其监管机制的全面洞察。这一限制就产生了 因为哺乳动物体内大约600种泛素连接酶中的大多数在很大程度上 没有特征的。我们的实验室一直致力于库林环泛素连接酶(CRL)的研究。 复合体控制着细胞生命的三个基本维度：增殖、存活和 差异化。我们在阐明如何、何时、何地和大多数 重要的是，为什么CRL调节关键细胞调节因子的降解。在我的研究中 实验室最初专注于哺乳动物细胞周期的定时调节范例。 通过我们几年前建立的泛素-蛋白酶体系统。我们有 自将我们的研究扩展到五个领域：(I)细胞信号转导，(Ii)细胞周期控制，(Iii) DNA损伤反应，(Iv)肿瘤学，和(V)生物钟。我们的这一扩展 兴趣已经成为可能，这要归功于我们的发现驱动的方法，与 更常见的假设驱动的方法是不偏不倚的。然而，遗传学和 蛋白质组学筛查不是我们的最终目标，但它们引导我们解释潜在的生物学 概念和机制。重要的是，它们经常把我们引向意想不到的、未被探索的新事物 领地，打开我们的视野。总而言之，我们使用了一种全面的、跨学科的 开拓新天地并取得革命性发现的方法将提供新的 对基本生物过程的机械洞察，特别是那些 由CRLS监管。目前拟议的研究将涵盖所有的机理研究 在我们实验室进行的有关上述I-III区域的测试。特别是，我们将利用我们的 在泛素领域发现CRL的分子机制方面的公认专业知识 控制信号转导通路、自噬、细胞周期进程和DNA修复。 此外，我们将进行生化、细胞和体内分析，以阐明CRL是如何 调节以在不同的细胞命运之间切换的功能。这些发现将极大地 促进我们对关键细胞过程的正确执行的理解，潜在地 阐明人类疾病的病因和治疗方法。