Regulation of Distinc Actin Nucleation Mechanisms in Immune Cell Functions

免疫细胞功能中不同肌动蛋白成核机制的调节

基本信息

批准号：
8136243
负责人：
William Boyd Butler
金额：
$ 24.65万
依托单位：
TEXAS TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136243
关键词：
Actins Adhesions Affect Binding Biological Assay Bone Marrow Cancer Patient Cell physiology Cells Clinical Research Complex Confocal Microscopy Cytolysis Cytoplasmic Granules Cytoskeleton Engraftment Event Extracellular Matrix Proteins Extravasation Genetic Hematopoietic Homologous Gene Immune Immunologic Surveillance Immunotherapy Instruction Ligands Link Lipid Bilayers Lytic Mediating Microfilaments Microtubules Mutation Natural Killer Cells Phase Phosphorylation Play Process Proteins Recruitment Activity Regulation Role Signal Transduction Signaling Protein Stimulus Synapses System Techniques Tetanus Helper Peptide Total Internal Reflection Fluorescent Tyrosine Tyrosine Phosphorylation cancer cell clinically relevant human EMS1 protein killings meetings migration mutant prevent receptor response small hairpin RNA success synaptogenesis tumor

项目摘要

Regulated actin and microtubule dynamics are critical components of immune cell functions, as genetic and pharmacological inhibition of cytoskeletal dynamics renders Immune cells incapable of performing many of their effector functions. Actin assembly regulation is a complex process that involves many proteins including actin nucleators as well as their activators and effectors. The exact role and distinct modes of actin nucleation have yet to be elucidated in immune cells and how these processes affect immune cell functions. Activators of actin nucleation including cortactin have been largely studied in cells of non-hematopoietic lineage. However, in cells of hematopoietic lineage, adhesion, migration and actin cytoskeletal dynamics are highly regulated to prevent unwarranted immune cell functions. Arp2/3 and formins are two distinct actin nucleators and HS1 is a known activator of Arp2/3, yet their roles in immune cell functions and in particular natural killer (NK) cells remains incompletely understood. In addition, microtubule dynamics are required for NK-mediated cytolysis and recently it has been observed that formins play a role in microtubule dynamics. Microtubules play a distinct role in the delivery of cytolytic granules to the lytic synapse and formins play a critical role in linking the actin and microtubule cytoskeletons. Therefore, this proposal will examine the roles of Arp2/3 and formins in cytoskeletal dynamics, both actin and microtubule, in distinct NK functions.

受调节的肌动蛋白和微管动力学是免疫细胞功能的关键成分，如遗传和药理抑制细胞骨架动力学使免疫细胞无法执行许多它们的效应器功能。肌动蛋白组装调节是一个复杂的过程，涉及许多蛋白质包括肌动蛋白成核及其活化剂和效应子。肌动蛋白的确切作用和不同的模式成核尚未在免疫细胞中阐明，以及这些过程如何影响免疫细胞功能。肌动蛋白成核的激活剂在内已在非脊髓性的细胞中进行了很大的研究血统。但是，在造血谱系细胞中，粘附，迁移和肌动蛋白细胞骨架动力学是高度调节以防止不必要的免疫细胞功能。 ARP2/3和Formins是两个不同的肌动蛋白 Nucleators和HS1是ARP2/3的已知激活剂，但它们在免疫细胞功能中的作用，尤其是天然杀手（NK）细胞仍未完全理解。此外，需要微管动力学 NK介导的细胞解析，最近观察到formins在微管动力学中起作用。微管在将细胞溶剂颗粒传递到裂解突触中起着独特的作用在连接肌动蛋白和微管细胞骨架上的关键作用。因此，该建议将检查角色在不同的NK函数中，肌动蛋白和微管中的Arp2/3和formins和formins。