PIP3-INDEPENDENT REGULATION OF AKT1 ACTIVITY IN T CELLS

T 细胞中 AKT1 活性的 PIP3 独立调节

基本信息

批准号：
8788798
负责人：
Yina Hsing Huang
金额：
$ 40.5万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788798
关键词：
AKT1 gene Affinity Aneurysm Autoimmune Diseases Autoimmunity Avidity B-Cell Activation Binding Binding Proteins Biological CD8B1 gene Calmodulin Cell Extracts Cell Maturation Cell Surface Receptors Cell Survival Cell physiology Cells Cellular biology Chemicals Child Coronary artery Data Defect Dependence Development Family Generations Genes Grant Head Health Homologous Gene Human Immune Immune response In Vitro Infiltration Inositol Kinetics Ligands Link Membrane Membrane Lipids Molecular Molecular Conformation Mucocutaneous Lymph Node Syndrome Mus PH Domain Pathway interactions Peripheral Phosphorylation Phosphotransferases Predisposition Production Protein Isoforms Protein-Serine-Threonine Kinases Proteins Proteomics Proto-Oncogene Proteins c-akt Proto-Oncogenes Receptor Signaling Regulation Regulatory T-Lymphocyte Relative (related person)Reporting Role Second Messenger Systems Signal Transduction Signaling Protein Single Nucleotide Polymorphism T-Cell Development T-Cell Immunodeficiency T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TEC Protein Tyrosine Kinase Testing Thymocyte Selection Tissues analog cell growth in vivo migration mutant neutrophil novel platelet protein P47 protein function response second messenger therapeutic target thymocyte

项目摘要

DESCRIPTION (provided by applicant): IP4 is a newly discovered second messenger that we identified to be critical for T cell development and activation. How IP4 transmits T cell receptor signals to induce thymocyte maturation remains unclear. Its chemical similarity to the membrane lipid PIP3 suggests that it co-regulates PIP3-effectors, including the serine/threonine kinase AKT. In this grant, we propose that AKT is an important effector pathway downstream of IP4 that contributes to the development of mature CD4 or CD8 T cells and regulatory T cells. We hypothesize that IP4 promotes AKT activity through release of active AKT from the membrane and by facilitating AKT binding to Calmodulin, a Ca2+ sensing regulator of protein function. To test this hypothesis, we present three specific aims. In the first, we will characterize AKT binding to IP4 and PIP3 individually and by competitive inhibition analysis. Second, we will determine how IP4 regulates AKT localization, activation and phosphorylation of downstream effectors. Lastly, we will examine the importance of Calmodulin binding on AKT function in vivo and determine its dependence on IP4. We hope that elucidating the mechanism by which IP4 regulates AKT activity will allow a better understanding of how developmental signals precisely and differentially induce AKT activation to promote the maturation of different T cell subsets. Our long term objective is to characterize how IP4 relays signals from T cell surface receptors to direct specific and protective immune responses.

描述（由申请人提供）：IP4是新发现的第二使者，我们确定对T细胞开发和激活至关重要。 IP4如何传输T细胞受体信号诱导胸腺细胞的成熟尚不清楚。它与膜脂质PIP3的化学相似性表明它共同调节PIP3效应，包括丝氨酸/苏氨酸激酶Akt。在这笔赠款中，我们建议AKT是IP4下游的重要效应途径，有助于成熟的CD4或CD8 T细胞和调节性T细胞的发展。我们假设IP4通过从膜上释放主动AKT并促进AKT与Calmodulin结合，这是蛋白质功能的Ca2+传感调节剂，从而促进AKT活性。为了检验这一假设，我们提出了三个具体目标。首先，我们将分别和竞争性抑制分析分别表征与IP4和PIP3的AKT结合。其次，我们将确定IP4如何调节下游效应子的AKT定位，激活和磷酸化。最后，我们将研究钙调蛋白结合对体内Akt功能的重要性，并确定其对IP4的依赖性。我们希望阐明IP4调节AKT活性的机制，将更好地理解发育信号如何精确和差异地诱导Akt激活以促进不同T细胞子集的成熟。我们的长期目标是表征IP4如何从T细胞表面受体传递信号到直接特定和保护性免疫反应。