Live-cell Activity Architecture in Cancer

癌症中的活细胞活性结构

• 批准号: 9319218
• 负责人: Jin Zhang
• 金额: $ 93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319218
• 关键词: Architecture; Behavior; Biochemical; Biochemical Process; Biophysical Process; Cell physiology; Cells; Cessation of life; Cyclic AMP-Dependent Protein Kinases; Development; Environment; Enzymes; Family; Generations; Goals; Growth Factor; Hormones; Lead; Malignant Neoplasms; Mechanics; Methods; Molecular; Mutation; Normal Cell; Oncogenic; Phosphotransferases; Play; Proteins; Research; Role; Technology; Testing; Therapeutic Intervention; Treatment Efficacy; cell growth; nanomachine; new technology; optogenetics; programs; public health relevance; single molecule; technological innovation; tumorigenesis

 DESCRIPTION (provided by applicant): The assembly/disassembly and enzymatic activities of protein nanomachines underlie all cellular functions, and dysregulated nanomachines are the ultimate culprits in cancer. Our proposed research seeks to establish a new conceptual framework to specifically understand the cellular organization of molecular activities. We hypothesize that cellular biochemical activities are spatially organized into an "activity architecture" via the specific organization of active molecules and their regulatory partners. This activity architecture, together with the structural and mechanical architecture of the cell, encodes all the information needed to drive cellular function. We further hypothesize that perturbations to this activity architecture, even by a few dysregulated driver molecules, could lead to detrimental effects on cellular functions such as loss of control over cell growth, divisio and death. The key technological innovation of our research program is to develop and utilize a new generation of enabling technologies for visualizing and perturbing biochemical and biophysical processes in the native environment of a living cell. Enabled by these new technologies, we will start testing our general hypothesis by elucidating the spatial organization of the enzymatic activities of protein kinases, a family of enzymes that play critical roles in normal cell physiology and tumorigenesis. We will further probe how this kinase activity architecture is dynamically modulated by hormones and growth factors and perturbed by oncogenic mutations. We will also use our single- molecule optogenetic method to probe the connectivity, robustness and sensitivity of the activity architecture. We expect the successful completion of this study will yield a suite of new, transformative technologies with the potential to change the way that biochemical processes are studied in the context of cellular organization. Most importantly, establishing this new conceptual framework of a spatially organized activity architecture should produce a paradigm shift with respect to our understanding of the behaviors of active molecules in their native environment. Characterization of "dys-organized" activity architectures in cancers should lead to the development of more effective therapeutic treatments that target such dysregulation.

 描述（由申请人提供）：蛋白质纳米机器的组装/分解和酶活性是所有细胞功能的基础，而失调的纳米机器是癌症的最终罪魁祸首。我们提出的研究旨在建立一个新的概念框架来专门了解分子的细胞组织。我们探索了细胞生化活动通过活性分子及其调节伙伴的特定组织在空间上组织成“活动架构”。 活动架构与细胞的结构和机械架构一起编码驱动细胞功能所需的所有信息，我们进一步发现，即使是一些失调的驱动分子，对这种活动架构的干扰也可能导致对细胞功能的困扰。例如对细胞生长、分裂和死亡的控制丧失，我们研究项目的关键技术创新是开发和利用新一代的使能技术来可视化和扰动活细胞原生环境中的生化和生物物理过程。通过这些新的技术，我们将通过阐明蛋白激酶的酶活性的空间组织来开始测试我们的一般假设，蛋白激酶是在正常细胞生理学和肿瘤发生中发挥关键作用的酶家族，我们将进一步探讨如何动态调节这种激酶活性结构。我们还将使用我们的单分子光遗传学方法来探测活性结构的连接性、稳健性和敏感性，我们预计这项研究的成功完成将产生一系列结果。新的变革性技术有可能改变细胞组织背景下生化过程的研究方式。最重要的是，建立这种空间组织活动架构的新概念框架应该会产生我们对行为理解的范式转变。癌症中“组织失调”活性结构的表征应该会导致针对这种失调的更有效的治疗方法的开发。