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.

多细胞组织中细胞结构的动态组织 大多数人类癌症来源于上皮组织。在癌中， 转移，这是肿瘤进展的终末阶段的特征， 超过90%的死亡率。导致肿瘤细胞转移的事件已经被研究 通过对肿瘤细胞行为的研究，这表明肿瘤侵袭可以通过 集体细胞迁移。集体迁移的肿瘤细胞与单个细胞有许多相似之处， 迁移和动态重塑上皮组织在发展过程中。虽然 单细胞迁移的信号传导机制已被广泛研究， 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的组织化， 在组织的平面中的行为，称为平面极性的性质。早期的果蝇 胚胎是一个简单的多细胞上皮细胞，其中蛋白质的平面极化定位 参与收缩和粘连的细胞会导致组织发生形状的巨大变化， 产生一个伸长的头到尾的身体轴。这个项目的目标是剖析信号 平面极性的建立和平面极化细胞的调控机制 在这个动态重塑的组织中重新排列。具体来说，这些研究将确定 将相邻细胞之间的相互作用转化为空间上的分子途径 调节肌动蛋白细胞骨架组织的变化。在目标1中，我将执行损失， 获得功能研究，以确定参与调节平面 在轴伸长过程中参与连接重塑的蛋白质的极化定位， 集中于调节肌动球蛋白细胞骨架的组织和动力学的蛋白质。在 目标2，我将研究这些过程如何受到局部细胞提供的细胞外信号的调节 细胞之间的相互作用，以定向和协调多细胞内的肌动蛋白重组 人口这些研究将揭示外部信号是如何转化为平面极化的 上皮细胞发育过程中细胞行为的变化，并将提供深入了解 控制空间调节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， 体内肌动球蛋白动力学有助于阐明控制集体细胞的机制， 在其他情况下的行为，如在上皮肿瘤的侵袭和转移期间。

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