Development of functional synthetic biomolecular condensates.

功能性合成生物分子缩合物的开发。

• 批准号: 10028849
• 负责人: Allie C Obermeyer
• 金额: $ 39.45万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028849
• 关键词: Address; Amino Acid Sequence; Binding; Cataract; Cations; Cell physiology; Cells; Chemicals; Development; Diffusion; Disease; Electrostatics; Engineering; Environment; Enzymes; Eukaryotic Cell; Gene Expression; Goals; In Vitro; Individual; Liquid substance; Malignant Neoplasms; Metabolic Pathway; Methods; Molecular; Nerve Degeneration; Organelles; Phase; Phase Transition; Physical Function; Play; Prokaryotic Cells; Property; Proteins; Research; Signal Transduction; imaging modality; improved; in vivo; insight; intermolecular interaction; macromolecule; molecular scale; physical property; programs; protein function; protein structure; synthetic biology

PROJECT SUMMARY Membraneless organelles, or biomolecular condensates, have emerged as a strategy to organize the contents of prokaryotic and eukaryotic cells. These phase separated compartments play key roles in a range of cellular functions – from signaling to tuning metabolic pathways or controlling gene expression – yet there are still questions about the fundamental mechanisms for their formation, dynamics, and function. The relationship between condensate molecular properties and function is not yet understood, but this could provide an avenue to treat diseases that involve dysregulated protein condensates (neurodegeneration, cataracts, cancer). Our research proposes to develop functional synthetic biomolecular condensates in order to address several over- arching questions: How do specific intermolecular interactions (electrostatic, cation-π, etc.) contribute to protein phase transitions? How do protein sequence and structure influence the physical properties and function of the condensed phase? Is there a connection between the materials properties and the function of biomolecular condensates? Semi-synthetic biomolecular condensates will allow us to evaluate how molecular interactions in the condensed phase contribute not only to the dynamics of the phase but also to small and macromolecule partitioning, and ultimately the function of endogenous biomolecular condensates. The goals of the proposed research program are to create enzymatically active synthetic membraneless organelles in vitro and in vivo. New materials with varied chemical environments will be prepared and new methods for imaging protein condensates at the molecular scale will be established. These advances will help us to understand how protein sequence influences function at both the microscale (e.g. of an individual enzyme) and the mesoscale (e.g. of a condensed phase cellular compartment). Engineering orthogonal biomolecular condensates has the potential to impact our understanding of the function of native biomolecular condensates and provide a synthetic biology platform to artificially regulate information flow in the cell.

项目摘要 无膜细胞器，或生物分子凝聚物，已经成为组织内容物的一种策略 原核细胞和真核细胞。这些相分离的区室在一系列细胞内的细胞内起着关键作用。 功能-从信号到调节代谢途径或控制基因表达-但仍然存在 关于其形成、动力学和功能的基本机制的问题。的关系 冷凝物的分子性质和功能之间的关系尚不清楚，但这可以提供一种途径， 治疗涉及蛋白质缩合物失调的疾病（神经变性、白内障、癌症）。我们 研究提出开发功能性合成生物分子缩合物，以解决几个过度- 特殊的分子间相互作用（静电、阳离子-π等）有助于蛋白质 相变？蛋白质序列和结构如何影响蛋白质的物理性质和功能？ 凝聚相？材料性能与生物分子功能之间是否存在联系 冷凝物？半合成生物分子凝聚物将使我们能够评估分子间的相互作用， 凝聚相不仅对相的动力学有贡献，而且对小分子和大分子的动力学也有贡献。 分配，并最终内源性生物分子凝聚物的功能。拟议的目标 研究计划是在体外和体内创造具有酶活性的合成无膜细胞器。新 将制备具有不同化学环境的材料，并开发新的蛋白质凝聚物成像方法 在分子尺度上的研究将被建立。这些进展将帮助我们理解蛋白质序列 影响微观尺度（例如单个酶）和中尺度（例如浓缩酶）的功能 相细胞隔室）。工程正交生物分子凝聚物有可能影响我们的研究。 了解天然生物分子缩合物的功能，并提供合成生物学平台， 人工调节细胞中的信息流。