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，由一个浓缩的网络组成， 蛋白质和核酸，划分细胞生物化学。建立一个精确的分子 组成对于冷凝物的生物功能至关重要。特别是，细胞必须组装（a） 在共享的环境中共存的不同组成的冷凝物，或（B）共存的 在同一个冷凝物中有不同的成分。在这两种情况下，细胞指定 成分的同一性知之甚少。在这个建议中，我将研究两种类型的生物 “表面”，（a）二维脂质膜和（B）一维长非编码RNA聚合物， 确定凝析油特性并指示不同层的形成。我假设每种表面 通过以不同的方式修饰RNA结构来调节缩合物的组成和功能。研究：In Aim 1，我将研究膜表面如何修饰RNA结构，以控制冷凝物的身份和调节 mRNA在细胞质中的翻译。在目标2中，我将研究一个长的非编码RNA的结构特征是如何 控制具有离散层的缩合物的形成并调节mRNA在细胞核中的保留。整体 其结果将是对细胞如何组装mRNA关键区室的增强的机械理解 功能培训：我将在剑桥查佩尔山与Amy Gladfelter教授一起完成我的培训。培训期间 在此期间，我将与创新的合作者一起工作，以获得新的技能，使我能够探测和操纵 RNA结构和剖析生物分子凝聚的分子驱动力。这些技能将 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，我将学习强大的战略，（1）地图RNA结构与凯文周在斯坦福大学;（2）研究长期 非编码RNA与Mauro Calabrese在2009年;（3）检查mRNA翻译的空间调节， 杜克大学的Chris Nicchitta;（4）与Krishna一起开发生物自组装的数学模型 哈佛大学的施里尼瓦斯。Gladfelter是一位支持和鼓舞人心的导师， 创造力和协作。查佩尔山是世界级RNA生物学的中心， 向有经验的科学家学习的机会。这个K99/R 00奖将使我能够追求令人兴奋的新 研究方向超出了我的核心技能，形成强大的合作与领先的实验室，并沉浸在自己 通过各种课程，研讨会，讲习班和会议在新的学科。影响到公共 健康：近年来，生物分子凝聚过程引起了人们的浓厚兴趣，部分原因是 它在形成病理性聚集体中的作用，病理性聚集体引起神经变性疾病， 侧索硬化我的工作将揭示细胞控制组成的基本机制， 生物分子凝聚物的涌现功能。通过这些发现，我希望能帮助 临床干预措施，以治疗由破坏这一重要细胞现象引起的疾病。