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 自从发现泛素 - 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见解。出现了这种限制 因为哺乳动物中的大多数大约600个泛素连接酶 未表征。我们的实验室专注于Cullin环泛素连接酶（CRL）如何 复合物控制细胞寿命的三个基本维度：增殖，生存和 分化。我们在阐明如何，何时，地点和大多数方面发挥了核心作用 重要的是，为什么CRL介导关键细胞调节剂的降解。我的研究 实验室最初着重于哺乳动物细胞周期定时调节的范式 由泛素 - 蛋白酶体系统，我们几年前建立了。我们有 由于将我们的研究扩展到五个研究领域：（i）细胞信号传导，（ii）细胞周期控制，（iii） DNA损伤反应，（IV）肿瘤学和（v）昼夜节律。我们的这种扩展 由于我们以发现驱动的方法，与之相比 更常见的假设驱动的方法是公正的。然而，遗传学和 蛋白质组学筛选不是我们的最终目标，但是它们指导我们解释潜在的生物学 概念和机制。重要的是，它们经常导致我们出乎意料且未开发 领土，开放我们的视野。总而言之，我们使用全面的跨学科 打破新的理由并进行变革性发现的方法，以提供新的 对基本生物学过程的机械洞察，尤其是那些过程 由CRL监管。当前提出的研究将涵盖所有机械研究 在我们的实验室涉及上述I-III领域的领域。特别是，我们将利用我们的 在泛素领域公认的专业知识，以发现CRLS的分子机制 控制信号转导途径，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的方式 被调节可作为不同细胞命运之间的切换。这些发现将大大 促进我们对关键细胞过程正确执行的理解，可能 阐明了人类疾病的病因和治疗方法。