Cellular surfaces as regulators of biomolecular condensate assembly

细胞表面作为生物分子凝聚体组装的调节剂

• 批准号: 10639551
• 负责人: Wilton Thomas Snead
• 金额: $ 10.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639551
• 关键词: Acceleration; Amyotrophic Lateral Sclerosis; Architecture; Award; Binding Proteins; Biochemistry; Biological; Biological Models; Biological Process; Biology; Cell Cycle; Cell Nucleus; Cell physiology; Cells; Clinical; Collaborations; Communities; Creativeness; Cytoplasm; DNA; Discipline; Disease; Educational workshop; Endoplasmic Reticulum; Environment; Fostering; Foundations; Freedom; Heterogeneity; Human; Intervention; Knowledge; Learning; Length; Lipid Bilayers; Liquid substance; Maps; Measures; Membrane; Membrane Lipids; Mentors; Messenger RNA; Mission; Molecular; Molecular Conformation; Morphology; Neurodegenerative Disorders; Nuclear; Nuclear Matrix; Nucleic Acids; Outcome; Pathologic; Physical condensation; Polymers; Post-Transcriptional Regulation; Process; Property; Proteins; Public Health; Quantitative Microscopy; RNA; RNA Conformation; RNA Probes; RNA-Binding Protein FUS; Radial; Regulation; Research; Role; Sampling; Scientist; Sorting; Specific qualifier value; Structure; Surface; Training; Translations; United States National Institutes of Health; Universities; Untranslated RNA; Work; career; cell assembly; clinical development; disability; driving force; experience; flexibility; innovation; interest; mRNA Translation; mathematical model; meter; novel strategies; physical property; reconstitution; recruit; self assembly; skills; symposium; two-dimensional

PROJECT SUMMARY. Introduction: Biomolecular condensates, composed of a concentrated network of proteins and nucleic acids, compartmentalize cellular biochemistry. The establishment of a precise molecular composition is critical for the biological functions of condensates. In particular, cells must assemble either (a) coexisting condensates of distinct composition within a shared environment or (b) coexisting sub-layers of distinct composition within the same condensate. In both cases, the mechanisms by which cells specify compositional identity are poorly understood. In this proposal, I will examine how two types of biological “surfaces,” (a) two-dimensional lipid membranes and (b) one-dimensional long noncoding RNA polymers, establish condensate identity and dictate the formation of distinct layers. I hypothesize that each type of surface regulates condensate composition and function by modifying RNA structure in distinct ways. Research: In Aim 1, I will examine how membrane surfaces modify RNA structure to control condensate identity and regulate mRNA translation in the cytoplasm. In Aim 2, I will examine how the structural features of a long noncoding RNA control the formation of condensates with discrete layers and regulate mRNA retention in the nucleus. The overall outcome will be an enhanced, mechanistic understanding of how cells assemble key compartments of mRNA function. Training: I will complete my training with Prof. Amy Gladfelter at UNC Chapel Hill. During the training period, I will work with innovative collaborators to acquire new skills that will enable me to probe and manipulate RNA structure and dissect the molecular driving forces of biomolecular condensation. These skillsets will accelerate discovery during the remainder of my training and form the foundation for my independent lab. Specifically, I will learn powerful strategies to (1) map RNA structure with Kevin Weeks at UNC; (2) study long noncoding RNAs with Mauro Calabrese at UNC; (3) examine the spatial regulation of mRNA translation with Chris Nicchitta at Duke University; and (4) develop mathematical models of biological self-assembly with Krishna Shrinivas at Harvard University. Environment: Prof. Gladfelter is a supportive and inspiring mentor who fosters creativity and collaboration. UNC Chapel Hill is a hub for world-class RNA biology and will provide valuable opportunities to learn from experienced scientists. This K99/R00 award will enable me to pursue exciting new research directions beyond my core skillsets, form strong collaborations with leading labs, and immerse myself in new disciplines through a variety of courses, seminars, workshops, and conferences. Impact on Public Health: The process of biomolecular condensation has generated intense interest in recent years, in part due to its role in the formation of pathological aggregates that cause neurodegenerative diseases such as amyotrophic lateral sclerosis. My work will uncover fundamental mechanisms by which cells control the composition and emergent functions of biomolecular condensates. Through these discoveries, I hope to aid in the development of clinical interventions to treat diseases caused by disruptions to this important cellular phenomenon.

项目摘要。简介：生物分子凝聚物，由集中的网络组成 蛋白质和核酸，划分细胞生物化学，建立精确的分子。 组成对于凝聚物的生物学功能至关重要，特别是，细胞必须组装（a）。 共享环境中不同成分的共存凝结物或（b）共存的子层 在这两种情况下，细胞指定的机制不同。 人们对成分同一性知之甚少，在本提案中，我将研究两种类型的生物如何。 “表面”，（a）二维脂质膜和（b）一维长非编码RNA聚合物， 建立凝结物特性并决定不同层的形成。 通过以不同的方式改变 RNA 结构来调节凝结物的组成和功能。 研究：In Aim。 1，我将研究膜表面如何改变RNA结构来控制凝结物身份并调节 在目标 2 中，我将研究长非编码 RNA 的结构特征。 控制离散层凝聚物的形成并调节 mRNA 在细胞核中的保留。 结果将是对细胞如何组装 mRNA 关键区室的增强的机械理解 培训：我将在北卡罗来纳大学教堂山分校的 Amy Gladfelter 教授的指导下完成培训。 在此期间，我将与创新合作者合作，获得新技能，使我能够探索和操纵 RNA 结构并剖析生物分子缩合的分子驱动力。 在我剩余的培训期间加速发现，并为我的独立实验室奠定基础。 具体来说，我将学习强大的策略：(1) 与 UNC 的 Kevin Weeks 一起绘制 RNA 结构图；(2) 长期学习； 与 UNC 的 Mauro Calabrese 一起研究非编码 RNA；(3) 研究 mRNA 翻译的空间调控 杜克大学的 Chris Nicchitta；以及 (4) 与 Krishna 一起开发生物自组装的数学模型 哈佛大学的 Shrinivas 环境：Gladfelter 教授是一位支持和鼓舞人心的导师，致力于培养人才。 北卡罗来纳大学教堂山分校是世界一流的 RNA 生物学中心，将提供宝贵的创造力和协作能力。 向经验丰富的科学家学习的机会将使我能够追求令人兴奋的新事物。 研究方向超出了我的核心技能，与领先的实验室形成强有力的合作，并让自己沉浸其中 通过各种课程、研讨会、讲习班和会议了解新学科。 健康：近年来，生物分子缩合过程引起了人们的强烈兴趣，部分原因是 它在导致神经退行性疾病（如肌萎缩侧索硬化症）的病理聚集体形成中的作用 我的工作将揭示细胞控制成分和功能的基本机制。 通过这些发现，我希望能够帮助开发生物分子凝聚体的新兴功能。 治疗因这种重要细胞现象破坏而引起的疾病的临床干预措施。