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

• 批准号: 8090261
• 负责人: EDWARD Y SKOLNIK
• 金额: $ 31.15万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/8090261
• 关键词: 1-Phosphatidylinositol 3-Kinase; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; B-Cell Activation; 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; 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; Viral Tumor Antigens; 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

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（由申请方提供）：Ca 2+激活的K+通道KCa 3.1是Ca 2+内流以及随后B和T细胞激活所必需的。KCa3.1的抑制剂正在开发中，用于治疗自身免疫性疾病和移植排斥反应，这强调了了解这些通道如何调节的重要性。我们对KCa3.1调节的研究揭示了一种全新的信号通路，该通路是人类CD 4 T细胞重新激活所必需的。该途径包括一种潜在的新型磷脂酰肌醇3激酶（PI 3 K）亚型，磷脂酰肌醇3-磷酸（PI（3）P）和一种哺乳动物组氨酸激酶，核苷二磷酸激酶B（NDPK-B），它们是KCa 3.1通道激活所必需的。我们发现NDPK-B在PI（3）P下游通过磷酸化KCa 3.1羧基末端（CT）尾的H358来激活KCa 3.1。此外，我们已经鉴定了两种新的T细胞活化负调控因子，PI（3）P磷酸酶肌微管蛋白相关蛋白6（MTMR 6）和组氨酸磷酸酶磷酸组氨酸磷酸酶-1（PHPT-1），它们分别通过使PI（3）P和KCa 3.1去磷酸化来抑制KCa 3.1。该提案的主要目标是进一步探索这些分子调节KCa3.1的机制及其与T细胞活化和疾病的生物学相关性。特异性目的（SA）1将确定CD 4 T细胞中的信号传导途径，该途径对于产生介导KCa 3.1通道激活的PI（3）P池至关重要，以及PI（3）P在上游发挥作用以调节NDPK-B的机制。SA 2将确定T细胞受体（TCR）刺激是否调节NDPK-B、KCa 3.1、MTMR 6和在SA 1中鉴定的PI 3 K同种型向免疫突触（IS）的再分布，以及这在KCa 3.1通道活性调节中所起的作用。SA 3将鉴定负调节KCa3.1通道活性的组氨酸磷酸酶及其在T细胞生物学中的作用。我们最近的数据表明，组氨酸磷酸酶PHPT-1和磷赖氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）是KCa 3.1的负调节剂，并且通过使KCa 3.1的CT中的组氨酸358（H358）去磷酸化来逆转NDPK-B对KCa 3.1的激活。是Ca 2+内流和随后的B和T细胞活化所必需的。KCa3.1的抑制剂正在开发中，用于治疗自身免疫性疾病和移植排斥反应，这强调了了解这些通道如何调节的重要性。 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，其作为KCa3.1通道活性的正调节剂和负调节剂发挥作用。我们发现，用正调节KCa3.1的分子干扰细胞，可能会发现治疗移植排斥和自身免疫性疾病的新药物靶点。另一方面，我们发现的负调节KCa 3.1的分子的异常表达或活性可以为自身免疫性疾病提供新的见解。