Supplement to Support Diversity in Research

支持研究多样性的补充

• 批准号: 10596422
• 负责人: Stephanie Gupton
• 金额: $ 1.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596422
• 关键词: Actins; Address; Award; Biochemical; Biological Models; Cell Shape; Cell membrane; Cells; Cellular Structures; Characteristics; Computer Vision Systems; Cues; Cytoskeletal Proteins; Cytoskeleton; Data; Development; Environment; Event; Exocytosis; Filopodia; Frequencies; Genetic; Goals; Health; Knowledge; Lead; Machine Learning; Malignant Neoplasms; Mediating; Melanoma Cell; Membrane; Microfluidics; Microscopy; Microtubules; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Neoplasm Metastasis; Neuronal Plasticity; Neurons; Parents; Pathogenesis; Pathologic; Pathology; Peripheral; Phenotype; Phosphotransferases; Physiology; Play; Program Description; Proteins; Publishing; Quantitative Evaluations; Regulation; Research; Role; Shapes; System; TRIM Gene; Testing; Ubiquitination; Vesicle; Work; active control; cell motility; cell type; depolymerization; extracellular; genetic regulatory protein; melanoma; morphogens; neural network; neuron development; novel; polymerization; programs; protein transport; response; sensor; spatiotemporal; tool; trafficking; tumor progression; ubiquitin-protein ligase

PROGRAM DESCRIPTION The overarching research goal of my lab is to define cellular and molecular mechanisms mediating cellular shape change. Cellular shape change is a fundamental characteristic of metazoan cells, key to development, physiology, and pathology. The formation and plasticity of neural networks are key examples of cell shape change during development and physiology, whereas cell shape and motility goes awry in pathological conditions, such as melanoma. We study two main themes during cellular shape change: The active control of the cytoskeleton, which is acknowledged as critical to cellular shape change, and the concurrent remodeling of the plasma membrane, which is perhaps less well appreciated. Although many cytoskeletal and membrane remodeling components are known and their biochemical and structural characteristics described, we lack a systematic understanding of how these disparate systems are regulated and coordinated to orchestrate cellular shape change. Perhaps the most important problem in cell morphogenesis is understanding how cells perceive cues in their environment and convert this extracellular information into shape changes through coordinated cytoskeletal dynamics and plasma membrane remodeling; this is the focus of this proposal. Functions of small GTPases and kinases have been extensively studied in regulating cytoskeletal dynamics and membrane remodeling. Work from my lab identified an emerging role for E3 ubiquitin ligases in regulated cellular shape change. We identified two E3 ubiquitin ligases, TRIM9 and TRIM67, which regulate cytoskeletal and exocytic proteins and cellular shape changes in response to netrin. The extracellular morphogen netrin promotes neuronal morphogenesis and cancer progression. Despite these important consequences, we know little about how cells interpret netrin into shape changes. TRIM9 and TRIM67 provide an excellent opportunity to investigate the function of ubiquitination in cytoskeletal and membrane remodeling, and how these functions are coordinated during netrin triggered cell shape change and motility. TRIM9 and TRIM67 share similar sequences, localization, and interaction partners, however our studies identified distinct functions of these related proteins and antagonistic phenotypes associated with their deletion. The overarching goal of this program is to test the hypothesis that TRIM9 and TRIM67 coordinate cytoskeletal dynamics and exocytosis during netrin-dependent morphogenesis in multiple cell types. Since netrin plays roles in both neuronal development and cancer pathogenesis, our work will exploit developing neurons and migrating melanoma cells as model systems. Our preliminary and published data indicate both cell types respond to netrin and express TRIM9 and TRIM67. Our work will illuminate fundamental generalities and cell type specific mechanisms of shape change, providing mechanistic understanding of the coordination of the cytoskeleton and membrane trafficking during development and metastasis. This supplement seeks to promote diversity in our health related research.

程序说明 我实验室的总体研究目标是定义介导细胞形状的细胞和分子机制 改变。细胞形状变化是后生细胞的基本特征，是发育的关键， 生理学和病理学。神经网络的形成和可塑性是细胞形状的关键例子 发育和生理过程中的变化，而细胞的形状和运动性在病理学上出现问题 疾病，例如黑色素瘤。我们在细胞形状变化过程中研究了两个主要主题： 细胞骨架被认为对细胞形状的变化至关重要，并同时重塑 质膜，也许不太受赞赏。虽然许多细胞骨架和膜 重塑成分是已知的，其生化和结构特征描述了，我们缺乏 系统地了解这些不同的系统如何受到调节和协调以编排蜂窝 形状变化。细胞形态发生中最重要的问题也许是了解细胞如何感知 在其环境中提示，并通过协调将这些细胞外信息转换为形状变化 细胞骨架动力学和质膜重塑；这是该提议的重点。小的功能 GTPases和激酶已经在调节细胞骨架动力学和膜上进行了广泛的研究 重塑。我实验室的工作确定了E3泛素连接酶在调节的细胞形状中的新兴作用 改变。我们鉴定了两个E3泛素连接酶Trim9和Trim67，它们调节细胞骨架和外生细胞 蛋白质和细胞形状响应于Netrin。细胞外形态NETRIN促进神经元 形态发生和癌症进展。尽管有这些重要的后果，但我们对细胞如何了解 将Netrin解释为形状变化。 TRIM9和TRIM67提供了一个很好的机会来调查 泛素化在细胞骨架和膜重塑中的功能，以及这些功能如何协调 在Netrin期间，触发了细胞形状的变化和运动。 TRIM9和TRIM67共享类似的序列，本地化， 和互动伙伴，但是我们的研究确定了这些相关蛋白质的不同功能 拮抗表型与其缺失有关。该程序的总体目标是测试 假设TRIM9和TRIM67在Netrin依赖性期间坐标核骨骼动力学和胞吐作用 多种细胞类型的形态发生。由于Netrin在神经元发育和癌症中都起着作用 发病机理，我们的工作将利用发展中的神经元，并将黑色素瘤细胞作为模型系统。我们的 初步数据和已发布的数据表明两个细胞类型对Netrin响应，并表示Express TRIM9和TRIM67。我们的 工作将阐明基本的概括和细胞类型的特定形状变化机制，提供 在发育过程中对细胞骨架和膜运输协调的机械理解 和转移。这种补充旨在促进我们与健康有关的研究中的多样性。