PLC?s in B cell biology and autoimmunity

B 细胞生物学和自身免疫中的 PLC

• 批准号: 8076308
• 负责人: DEMIN WANG
• 金额: $ 39.94万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076308
• 关键词: Affect; Alleles; Apoptosis; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Cell Development; B-Lymphocytes; BLNK gene; Cell Maturation; Cellular biology; Cessation of life; Clonal Deletion; Complex; DNA Sequence Rearrangement; Data; Development; Disease; Embryo; Ensure; Enzymes; Excision; Exclusion; Genes; Health; Immunoglobulins; Immunologic Deficiency Syndromes; Individual; LCP2 gene; Lead; Ligation; Light; Lipids; Lymphopoiesis; MAPK14 gene; MAPK8 gene; Mature B-Lymphocyte; Mediating; Molecular; Mus; Pathogenesis; Pathway interactions; Phospholipase; Play; Positioning Attribute; Process; Protein Isoforms; Protein Tyrosine Kinase; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Research; Residual state; Role; Self Tolerance; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Staging; System; Testing; Transgenic Mice; adapter protein; anergy; autoreactive B cell; mouse model; novel; pre-B cell receptor; progenitor; public health relevance; rap1 GTP-Binding Proteins; receptor

DESCRIPTION (provided by applicant): Early B cell development and late B cell maturation are regulated by signals emanating from the pre-B cell receptor (BCR) and BCR, respectively. During maturation, B cell tolerance to self-antigens is established through clonal deletion, receptor editing and anergy, which are controlled by signals emanating from the BCR. Distorted pre-BCR/BCR signaling often results in defective B cell development, breakdown of B cell tolerance and development of immunodeficiency and autoimmune diseases. Signals from the pre-BCR/BCR that regulate B cell development and tolerance are not fully understood. Phospholipase C3 (PLC3) is an important lipid enzyme involved in pre-BCR/BCR signaling. PLC3 has two isoforms, PLC31 and PLC32. PLC32-deficient mice are viable and have impaired early and late B development. Our recent data find that PLC32 plays an important role in activation of light chain loci, editing of self-reactive receptors and induction of B cell anergy. PLC31 deficiency results in early embryonic death at midgestation, precluding analysis of its role in B cell development. However, our studies of PLC32-deficient mice that are heterozygous for PLC31-deficiency (PLC31PLC32-/-) indicate that PLC31 also plays an important role in B development. We have recently generated mice in which the PLC31 gene can be conditionally inactivated. With the mice that have genetically modified PLC31 and PLC32 genes, we are well-positioned to further study the individual and combined roles of PLC31/PLC32 in B lymphopoiesis, including tolerance establishment, and the mechanism by which both PLC3s regulate the process. We hypothesize that both PLC31 and PLC32 play an important role in pre- BCR/BCR-mediated functions and in establishing B cell tolerance. To test our hypothesis, we propose three specific aims. We will 1) determine the role of PLC31 and combined roles of PLC31 and PLC32 in pre- BCR-mediated early B cell development, allelic exclusion of IgH chain, activation of the IgL chain loci, and formation of the B cell repertoire, 2) determine the individual and combined roles of PLC31 and PLC32 in BCR- mediated B cell maturation, receptor editing and induction of anergy in B cells, and 3) study the upstream and downstream pathways of PLC31 and PLC32 during pre-BCR/BCR signaling. The proposed research seeks to understand the roles for the two PLC3 isoforms in B lymphopoiesis, especially tolerance establishment, and the mechanism by which they relay the signals from the pre-BCR/BCR. The study may provide new clues to the molecular pathogenesis of autoimmune diseases and help identify targets for specific therapies. PUBLIC HEALTH RELEVANCE This proposal seeks to understand the roles of two important signaling molecules PLC31 and PLC32 in the development of B lymphocytes, including the removal of autoreactive B cells, and the molecular mechanism by which PLC3s regulate these processes. The study may provide new clues to the molecular pathogenesis of autoimmune and immunodeficiency diseases, and help identify novel targets for specific therapies.

描述（由申请人提供）：早期 B 细胞发育和晚期 B 细胞成熟分别受前 B 细胞受体 (BCR) 和 BCR 发出的信号调节。在成熟过程中，B 细胞对自身抗原的耐受性是通过克隆删除、受体编辑和无反应性建立的，这些过程由 BCR 发出的信号控制。扭曲的前 BCR/BCR 信号传导通常会导致 B 细胞发育缺陷、B 细胞耐受性破坏以及免疫缺陷和自身免疫性疾病的发生。来自前 BCR/BCR 调节 B 细胞发育和耐受性的信号尚不完全清楚。磷脂酶 C3 (PLC3) 是参与前 BCR/BCR 信号传导的重要脂质酶。 PLC3 有两种同工型：PLC31 和 PLC32。 PLC32 缺陷小鼠仍能存活，但早期和晚期 B 发育受损。我们最近的数据发现，PLC32 在轻链位点激活、自身反应受体编辑和 B 细胞无反应性诱导中发挥着重要作用。 PLC31 缺陷会导致妊娠中期早期胚胎死亡，从而无法分析其在 B 细胞发育中的作用。然而，我们对 PLC31 缺陷杂合的 PLC32 缺陷小鼠 (PLC31PLC32-/-) 的研究表明，PLC31 在 B 发育中也发挥着重要作用。我们最近培育了 PLC31 基因可以有条件失活的小鼠。通过使用转基因 PLC31 和 PLC32 基因的小鼠，我们有能力进一步研究 PLC31/PLC32 在 B 淋巴细胞生成中的单独和组合作用，包括耐受性建立以及这两种 PLC3 调节该过程的机制。我们假设 PLC31 和 PLC32 在前 BCR/BCR 介导的功能和建立 B 细胞耐受性中发挥重要作用。为了检验我们的假设，我们提出了三个具体目标。我们将 1) 确定 PLC31 的作用以及 PLC31 和 PLC32 在 BCR 前介导的早期 B 细胞发育、IgH 链的等位基因排除、IgL 链位点的激活和 B 细胞库的形成中的作用，2) 确定 PLC31 和 PLC32 在 BCR 介导的 B 细胞成熟、受体编辑和 B 细胞无反应性诱导中的单独和组合作用 细胞，3) 研究前 BCR/BCR 信号传导过程中 PLC31 和 PLC32 的上下游通路。拟议的研究旨在了解两种 PLC3 亚型在 B 淋巴细胞生成中的作用，特别是耐受性建立，以及它们传递来自前 BCR/BCR 的信号的机制。该研究可能为自身免疫性疾病的分子发病机制提供新线索，并有助于确定特定治疗的靶点。公共健康相关性 该提案旨在了解两种重要信号分子 PLC31 和 PLC32 在 B 淋巴细胞发育中的作用，包括去除自身反应性 B 细胞，以及 PLC3 调节这些过程的分子机制。该研究可能为自身免疫和免疫缺陷疾病的分子发病机制提供新线索，并有助于确定特定治疗的新靶点。