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Regulation of T Cell Extravasation and Trafficking by the Actin Cytoskeleton

肌动蛋白细胞骨架对 T 细胞外渗和运输的调节

基本信息

批准号：
8825554
负责人：
Jordan Jacobelli
金额：
$ 26.95万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825554
关键词：
Actins Address Atypical lymphocyte Autoimmune Diseases Autoimmunity Basement membrane Blocking Antibodies Blood Circulation Blood Vessels Blood flow Cell Adhesion Molecules Cell Wall Cells Cellular biology Cues Cytoskeleton Data Development Disease Extravasation Family Filopodia Goals Homing Immigration Immune Immune response Immune system Immunologic Surveillance In Vitro Infiltration Integrins Knowledge Lead Left Lymphocyte Lymphocyte Function Malignant Neoplasms Mediating Mediator of activation protein Membrane Microfilaments Microscopy Molecular Multiple Sclerosis Neoplasm Metastasis Pericytes Play Process Proteins Role Shapes Site Stimulus T cell regulation T-Lymphocyte Testing Therapeutic Tissues Tumor-Derived Vascular Endothelial Cell Work base cell motility chemokine design in vivo insight interstitial leukemia/lymphoma lymphoid neoplasm migration novel novel therapeutics polymerization prevent rho GTP-Binding Proteins tool trafficking two-photon

项目摘要

Lymphocyte entry and migration in tissues play a critical role in immune surveillance and execution of effector functions as well as in diseases such as autoimmunity and metastasis of lymphocyte-derived malignancies. To localize within tissues lymphocytes extravasate across the vascular endothelial cell wall and follow environmental cues present in the tissues. During extravasation and migration within tissues, lymphocytes change shape and extend membrane protrusions, such as filopodia. However, little is known about the specific regulators of actin network remodeling necessary to generate these membrane protrusions and their specific role in T cell extravasation and interstitial migration. Our goal is to determine the mechanistic role of linear actin network remodeling in mediating T cell extravasation and interstitial motility. Most work on actin cytoskeletal remodeling has focused on upstream regulators, such as Rho-GTPases, which have pleiotropic effects on lymphocyte functions. Here instead, we focus on downstream effectors of linear actin network remodeling, Formin and Ena/Vasp proteins. These cytoskeletal effectors control the polymerization of linear actin filaments found in filopodia and we expect they will have a more defined function, such as enabling pathfinding, in regulating lymphocyte extravasation and interstitial migration. Lymphocytes undergo a migratory pathfinding process in order to find permissive extravasation sites along vascular walls and to follow environmental cues during interstitial migration. Filopodia can mediate sensing of environmental stimuli and have been suggested to play a role in lymphocyte trans-endothelial migration (TEM). However, the function of linear actin polymerization and of filopodia in promoting lymphocyte extravasation and interstitial motility remains unclear. We hypothesize that pathfinding during lymphocyte extravasation and interstitial motility requires cytoskeletal effectors of linear actin polymerization to generate specialized membrane protrusions, such as filopodia. We propose three aims to address this crucial gap in our understanding of how lymphocyte extravasation and interstitial motility are regulated by Formin and Ena/Vasp proteins: Aim 1: Determine the role of cytoskeletal effectors of linear actin polymerization in regulating pathfinding during TEM. Aim 2: Define the requirement for cytoskeletal effectors of linear actin polymerization in T cell extravasation and tissue infiltration in vivo. Aim 3: Determine the role of cytoskeletal effectors of linear actin polymerization in T cell pathfinding during interstitial motility and tissue localization. We will use complementary in vivo and in vitro approaches, including cutting-edge intra-vital 2-photon microscopy, to understand how Formin and Ena/Vasp cytoskeletal effectors regulate lymphocyte extravasation and interstitial motility. Determining the molecular basis by which the actin cytoskeleton regulates motility and extravasation of lymphocytes can lead to the design of new therapeutic tools to modulate lymphocyte trafficking and immune responses to treat autoimmunity or prevent metastasis of lymphocytic tumors.

淋巴细胞在组织中的进入和迁移在免疫监视和执行中起着至关重要的作用