Dynamic Organization of Cell Architecture in Multicellular Tissues

多细胞组织中细胞结构的动态组织

• 批准号: 10297826
• 负责人: Jay Shi
• 金额: $ 3.83万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297826
• 关键词: Actins; Actomyosin; Adhesions; Antibodies; Architecture; Atlases; Behavior; Binding; Biochemistry; Carcinoma; Catalytic Domain; Cell Culture Techniques; Cell Polarity; Cell membrane; Cell physiology; Cells; Characteristics; Cues; Cytoskeleton; Data; Defect; Development; Drosophila genus; Embryo; Embryonic Development; Epithelial; Event; Exhibits; Failure; Functional disorder; Genetic; Goals; Head; Human; In Vitro; Inflammatory; Instruction; Lead; Malignant Neoplasms; Measures; Modeling; Molecular; Mus; Myosin Type II; Neoplasm Metastasis; PTEN gene; Pathway interactions; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Play; Population; Process; Property; Protein Family; Proteins; Regulation; Reporter; Role; Shapes; Signal Pathway; Signal Transduction; Tail; Testing; Therapeutic; Tissues; Toll-like receptors; Transgenic Organisms; Translating; Tumor Cell Invasion; Tumor stage; Variant; Wing; cell behavior; cell motility; extracellular; gain of function; genetic manipulation; imaging approach; in vivo; insight; migration; mortality; mutant; neoplastic cell; neural plate; planar cell polarity; polarized cell; protein distribution; receptor; tumor; tumor behavior; tumor progression

PROJECT SUMMARY: Dynamic Organization of Cell Architecture in Multicellular Tissues The majority of human cancers are derived from epithelial tissues. In carcinomas, advancement to metastasis, which is characteristic of the terminal stages of tumor progression, accounts for over 90% of mortality. The events that lead to tumor cell metastasis have been investigated through studies of tumor cell behavior, which suggest that tumor invasion can initiate through collective cell migration. Collectively migrating tumor cells share many similarities with single cell migration and with dynamically remodeling epithelial tissues during development. However, while the signaling mechanisms underlying single cell migration have been extensively studied, the mechanisms that coordinate cell behaviors in dynamically remodeling multicellular tissues are less well understood. Tissue remodeling in epithelia requires the organization of cell polarity and behavior in the plane of the tissue, a property referred to as planar polarity. The early Drosophila embryo is a simple multicellular epithelium in which the planar polarized localization of proteins involved in contraction and adhesion cause the tissue to undergo dramatic changes in shape to produce an elongated head-to-tail body axis. The goal of this project is to dissect the signaling mechanisms involved in establishing planar polarity and regulating planar polarized cell rearrangements in this dynamically remodeling tissue. Specifically, these studies will determine the molecular pathways that translate interactions between neighboring cells into spatially regulated changes in the organization of the actin cytoskeleton. In Aim 1, I will perform loss and gain of function studies in order to identify key signaling pathways involved in regulating the planar polarized localization of proteins involved in junctional remodeling during axis elongation, with a focus on proteins that regulate the organization and dynamics of the actomyosin cytoskeleton. In Aim 2, I will study how these processes are regulated by extracellular cues provided by local interactions between cells to orient and coordinate actin reorganization across a multicellular population. These studies will reveal how external signals are translated into planar polarized changes in cell behavior during epithelial development and will provide insight into the fundamental mechanisms that control the spatially regulated organization and remodeling of the actin cytoskeleton in a multicellular tissue. Insight into the regulation of cell behavior and actomyosin dynamics in vivo can help to elucidate the mechanisms that control collective cell behavior in other contexts, such as during the invasion and metastasis of epithelial tumors.

项目摘要：多细胞组织中细胞结构的动态组织 大多数人类癌症来自上皮组织。在癌中，进步 转移是肿瘤进展的终末阶段的特征的转移 超过90％的死亡率。已经研究了导致肿瘤细胞转移的事件 通过研究肿瘤细胞行为，这表明肿瘤侵袭可以通过 集体细胞迁移。集体迁移肿瘤细胞与单细胞有许多相似之处 在发育过程中迁移并具有动态重塑上皮组织。但是， 已经对单细胞迁移的基础信号机制进行了广泛的研究， 在动态重塑多细胞组织中协调细胞行为的机制是 不太了解。上皮中的组织重塑需要细胞极性和 在组织平面中的行为，该特性称为平面极性。早期的果蝇 胚胎是一种简单的多细胞上皮，其中平面极化的蛋白质定位 参与收缩和粘附会导致组织发生巨大变化 产生伸长的头到尾轴轴。该项目的目的是剖析信号 涉及建立平面极性和调节平面极化细胞的机制 该动态重塑组织中的重排。具体而言，这些研究将确定 将相邻细胞之间的相互作用转化为空间的分子途径 调节肌动蛋白细胞骨架的组织的变化。在AIM 1中，我将造成损失， 功能研究的获得，以确定调节平面涉及的关键信号通路 轴伸长过程中涉及连接重塑的蛋白质的极化定位， 专注于调节肌动蛋白细胞骨架的组织和动力学的蛋白质。在 AIM 2，我将研究这些过程如何受到当地提供的细胞外提示的调节 细胞之间与方向和坐标肌动蛋白之间的相互作用跨多细胞重组 人口。这些研究将揭示如何将外部信号转换为平面两极化 上皮发育过程中细胞行为的变化，并将洞悉 控制空间调节的组织和重塑的基本机制 多细胞组织中的肌动蛋白细胞骨架。深入了解细胞行为的调节和 体内的肌动球蛋白动力学可以帮助阐明控制集体细胞的机制 在其他情况下的行为，例如上皮肿瘤的侵袭和转移。

项目成果

Toll receptors remodel epithelia by directing planar-polarized Src and PI3K activity.

• DOI: 10.1016/j.devcel.2021.04.012
• 发表时间: 2021-06-07
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Tamada M;Shi J;Bourdot KS;Supriyatno S;Palmquist KH;Gutierrez-Ruiz OL;Zallen JA
• 通讯作者: Zallen JA

An LRR Receptor-Teneurin System Directs Planar Polarity at Compartment Boundaries.

LRR 受体-Teneurin 系统在区室边界处引导平面极性。

• DOI: 10.1016/j.devcel.2019.08.003
• 发表时间: 2019
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Paré,AdamC;Naik,Pooja;Shi,Jay;Mirman,Zachary;Palmquist,KarlH;Zallen,JenniferA
• 通讯作者: Zallen,JenniferA