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Mechanisms of regulation of lymphocyte migration by actin cytoskeletal effectors

肌动蛋白细胞骨架效应器调节淋巴细胞迁移的机制

基本信息

批准号：
10583309
负责人：
Jordan Jacobelli
金额：
$ 49.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583309
关键词：
3-Dimensional Actins Adhesions Adhesives Adopted Autoimmune Autoimmunity Back Biological Models Blood Vessels Cell Communication Cell Nucleus Cells Characteristics Collagen Complement Complex Cues Cytoskeletal Proteins Cytoskeleton DNA Sequence Alteration Data Disease Embryonic Development Endothelial Cells Environment Environmental Risk Factor Extracellular Matrix Extravasation FMNL1 gene Face Family Generations Goals Homologous Gene Imaging Techniques Immune Immune response Immune system In Vitro Inflammatory Knowledge Ligands Location Lymphocyte Malignant Neoplasms Mediating Membrane Methods Microtubules Modeling Neoplasm Metastasis Nonmuscle Myosin Type IIA Pathologic Physiological Physiological Processes Play Protein Family Proteins Regulation Role Shapes T-Lymphocyte Testing Therapeutic Tissues Traction Force Microscopy Vascular Endothelium Work biophysical properties cancer cell cell motility cell type chemokine constriction immune function immune system function in vivo insight interstitial lymph nodes mechanical force migration novel pathogen three-dimensional modeling trafficking two photon microscopy wound healing

项目摘要

Lymphocytes must correctly localize to mount effective immune responses. To do this, lymphocytes migrate through tissue environments with very different biophysical characteristics, including extravasation from blood vessels and crawling through cell-packed or extracellular matrix-rich tissues. To navigate through these diverse environments, lymphocytes squeeze through constrictions and migrate in low- or high-adhesive environments. However, there is a key gap in the understanding of how specific cytoskeletal effectors regulate force generation, shape changes, and cell-cell or cell-matrix interactions during lymphocyte migration in different settings. Given their relevance to immune function, primary T lymphocytes are a highly significant model to investigate cytoskeletal regulation of the varying modes of amoeboid cell motility in three-dimensional (3D) environments. Formin family proteins are cytoskeletal effectors involved in mediating actin network remodeling. Formin-like-1 (FMNL1) and Diaphanous-homologue-1 (mDia1) are the two most highly expressed Formins in T cells. We recently determined that FMNL1 is required for T cell transendothelial migration (TEM) and trafficking to inflamed tissues. Interestingly, our preliminary data support that FMNL1 and mDia1 have distinct functions in T cell migration through confined environments. Our goal is to achieve a more comprehensive understanding of the mechanisms by which the cytoskeleton enables migration through diverse tissue environments by determining the mode of action of Formin proteins in T cell motility. We will investigate the mechanisms by which Formins generate mechanical forces during T cell migration, the contribution of Formins in promoting T cell nucleus passage through constrictions, and how Formins regulate T cell motility in vivo. We will also determine if FMNL1 and mDia1 act independently or in concert with the Arp2/3 complex and/or Myosin-IIA. Our hypothesis is that to promote migration through complex environments FMNL1 mediates force generation from the back of the T cell while mDia1 creates force and membrane protrusions at the cell front. To test this hypothesis, we will use a multi-faceted approach, including genetic/mutational approaches and advanced imaging techniques in complementary model systems in vitro and physiological environments in vivo. Aim 1: Determine the mechanisms by which FMNL1 and mDia1 promote T cell transendothelial migration. Aim 2: Determine how FMNL1 and mDia1 regulate T cell motility within 3D environments with diverse biophysical characteristics. Aim 3: Define how Formins regulate T cell extravasation and interstitial motility in vivo. Overall, our studies are significant in that they will advance our knowledge of T cell migration by providing new data to determine the mechanism of action of Formins in T cell motility and if they cooperate with Myosin-IIA to promote migration through environments with varied biophysical characteristics. Thus, this work has the potential to provide important insight into novel ways to therapeutically modulate lymphocyte migration, such as in autoimmune settings and inflammatory diseases.

淋巴细胞必须正确定位才能产生有效的免疫反应。为此，淋巴细胞通过具有非常不同的生物物理特征的组织环境迁移，包括外渗从血管和爬行通过细胞包装或细胞外基质丰富的组织。导航通过在这些不同的环境中，淋巴细胞通过收缩挤压并以低或高粘附性迁移。环境.然而，在理解特定的细胞骨架效应物如何调节淋巴细胞迁移过程中的力产生、形状变化和细胞-细胞或细胞-基质相互作用，不同的设置。考虑到它们与免疫功能的相关性，初级T淋巴细胞是一种非常重要的免疫细胞。模型研究细胞骨架调节的变形虫细胞运动的不同模式，在三维 (3D)环境.形成蛋白家族蛋白是参与介导肌动蛋白网络的细胞骨架效应子重塑形成素样蛋白1（FMNL 1）和透明质酸同源物1（mDia 1）是两种最高表达的 T细胞中的形成蛋白。我们最近确定FMNL 1是T细胞跨内皮迁移（TEM）所必需的。并运输到发炎的组织。有趣的是，我们的初步数据支持FMNL 1和mDia 1具有在T细胞迁移通过受限环境中的独特功能。我们的目标是实现一个更全面了解细胞骨架通过多种途径使迁移的机制组织环境通过确定形成蛋白在T细胞运动中的作用模式。我们将调查形成蛋白在T细胞迁移过程中产生机械力的机制， Formins在促进T细胞核通过缩窄中的作用，以及Formins如何调节T细胞运动， vivo.我们还将确定FMNL 1和mDia 1是独立作用还是与Arp 2/3复合物协同作用和/或肌球蛋白-IIA。我们的假设是，为了促进通过复杂环境的迁移，FMNL 1 介导T细胞背面的力产生，而mDia 1在T细胞背面产生力和膜突起。细胞前。为了验证这一假设，我们将使用多方面的方法，包括遗传/突变方法和先进的成像技术在体外和生理互补模型系统体内环境。目的1：探讨FMNL 1和mDia 1促进T细胞增殖的机制跨内皮迁移。目的2：确定FMNL 1和mDia 1如何在3D内调节T细胞运动性具有不同生物物理特性的环境。目的3：定义Formins如何调节T细胞外渗和体内间质运动性。总的来说，我们的研究是有意义的，因为它们将促进我们对T 通过提供新的数据来确定形成蛋白在T细胞运动中的作用机制，它们与肌球蛋白-IIA合作，促进通过具有不同生物物理学特性的环境的迁移，特色因此，这项工作有可能提供重要的见解，以新的方式来治疗调节淋巴细胞迁移，如在自身免疫性疾病和炎性疾病中。