New signaling pathways that positively and negatively regulate CD4 T cells via th

新的信号通路通过 th 正向和负向调节 CD4 T 细胞

基本信息

批准号：
7894642
负责人：
EDWARD Y SKOLNIK
金额：
$ 4.2万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894642
关键词：
1-Phosphatidylinositol 3-Kinase Antigen-Presenting Cells Antigens Autoimmune Diseases Binding Biological CD4 Positive T Lymphocytes Calcium-Activated Potassium Channel Cellular biology Data Development Diphosphates Disease Drug Delivery Systems Feedback Goals Graft Rejection Histidine Human In Vitro Learning Lipid Bilayers Location Mediating NME1 gene Nucleoside diphosphate kinase B Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Play Protein Isoforms Proteins Receptor Activation Recruitment Activity Regulation Role Side Signal Pathway T-Cell Activation T-Cell Receptor T-Lymphocyte Tail immunological synapse in vivo inhibitor/antagonist insight myotubularin novel overexpression phosphatidylinositol 3-phosphate phosphohistidine protein-histidine kinase public health relevance release of sequestered calcium ion into cytoplasm

项目摘要

DESCRIPTION (provided by applicant): The Ca2+-activated K+ channel, KCa3.1, is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. Our studies on the regulation of KCa3.1 have uncovered a completely new signaling pathway required for the reactivation of human CD4 T cells. This pathway includes a potentially novel phosphatidylinositol 3 Kinase (PI3K) isoform, phosphatidylinositol 3-Phosphate (PI(3)P), and a mammalian histidine kinase, Nucleoside Diphosphate Kinase B (NDPK-B), that are required for KCa3.1 channel activation. We found that NDPK-B functions downstream of PI(3)P to activate KCa3.1 by phosphorylating H358 in KCa3.1's carboxyterminal (CT) tail. Moreover, we have identified 2 new negative regulators of T cell activation, the PI(3)P phosphatase myotubularin related protein 6 (MTMR6) and the histidine phosphatase, phosphohistidine phosphatase-1 (PHPT-1), which inhibit KCa3.1 by dephosphorylating PI(3)P and KCa3.1 respectively. The major goal of this proposal is to further explore the mechanisms whereby these molecules regulate KCa3.1 and their biological relevance to T cell activation and disease. Specific Aim (SA) 1 will identify the signaling pathway in CD4 T cells that is critical for generating the PI(3)P pool that mediates KCa3.1 channel activation and the mechanism whereby PI(3)P functions upstream to regulate NDPK-B. SA2 will determine whether T cell receptor (TCR) stimulation regulates the redistribution of NDPK-B, KCa3.1, MTMR6, and the PI3K isoform identified in SA1 to the immunological synapse (IS), and the consequences this plays in the regulation of KCa3.1 channel activity. SA3 will identify the histidine phosphatase that negatively regulates KCa3.1 channel activity and its role in T cell biology. Our recent data indicates that the histidine phosphatases PHPT-1 and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) are negative regulators of KCa3.1 and function to reverse the activation of KCa3.1 by NDPK-B by dephosphorylating histidine 358 (H358) in the CT of KCa3.1.The Ca2+-activated K+ channel, KCa3.1, is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. Public Health Relevance: Our studies on the regulation of KCa3.1 have uncovered new signaling pathways that functions as both positive and negative regulators of KCa3.1 channel activity. Interfering pharmacologically with molecules we found that positively regulate KCa3.1 may identify novel drug targets to treat transplant rejection and autoimmune disease. On the flip side, abnormal expression or activity of molecules we identified that negative regulate KCa3.1 could provide new insight into autoimmune diseases.

描述（由申请人提供）：Ca2+流入和随后的B和T细胞的激活需要CA2+激活的K+通道KCA3.1。 KCA3.1的抑制剂正在开发中，以治疗自身免疫性疾病和移植排斥反应，强调了解如何调节这些渠道的重要性。我们对KCA3.1调节的研究发现了人类CD4 T细胞重新激活所需的全新信号通路。该途径包括一种潜在的新型磷脂酰肌醇3激酶（PI3K）同工型，磷脂酰肌醇3-磷酸（PI（3）P）和一种哺乳动物组氨酸激酶，核苷，核苷二磷酸二磷酸激酶B（NDPK-B），对于KCA3.1通道所需的。我们发现，PI（3）P下游的NDPK-B功能通过在KCA3.1的羧基末端（CT）尾部磷酸化H358来激活KCA3.1。此外，我们已经确定了T细胞激活的2个新的阴性调节剂，PI（3）P磷酸酶肌蛋白相关蛋白6（MTMR6）和组氨酸磷酸酶，磷酸组织磷酸酶-1（PHPT-1），抑制KCA3.1受dephosphorating Pi（3）PI（3）PI（3）PI（3）pi（3）pi（3）pi（3）pi（3）。该提案的主要目的是进一步探索这些分子调节KCA3.1及其与T细胞激活和疾病的生物学相关性的机制。具体目标（SA）1将确定CD4 T细胞中的信号通路，这对于生成PI（3）P池至关重要，该PI（3）P池介导KCA3.1通道激活以及PI（3）p在上游调节NDPK-B的机制。 SA2将确定T细胞受体（TCR）刺激是否调节NDPK-B，KCA3.1，MTMR6和SA1中的PI3K同工型的重新分布，并在SA1中鉴定为免疫突触（IS），以及在KCA3.1通道活性调节中扮演的后果。 SA3将识别负调节KCA3.1通道活性及其在T细胞生物学中的作用的组氨酸磷酸酶。我们最近的数据表明，组氨酸磷酸酶PHPT-1和磷酸酪氨酸磷酸磷酸性无机焦磷酸磷酸磷酸磷酸酶（LHPP）是KCA3.1的负调节剂，并通过去磷酸化的cantidine 358（h358）（H358）中的CCA+ KCA+ kca+ kca+ kca+ kca+ kca+ kca+ kca+ kca+ kca+ kca+ kcA.1。 KCA3.1是Ca2+流入和B和T细胞随后的激活所必需的。 KCA3.1的抑制剂正在开发中，以治疗自身免疫性疾病和移植排斥反应，强调了解如何调节这些渠道的重要性。公共卫生相关性：我们对KCA3.1调节的研究发现了新的信号通路，这些途径既是KCA3.1通道活动的正调节剂和负面调节剂。在药理学上干扰分子，我们发现积极调节KCA3.1可能会识别出新的药物靶标，以治疗移植排斥和自身免疫性疾病。另一方面，分子的异常表达或活性，我们确定负调节KCA3.1可以提供对自身免疫性疾病的新见解。