Regulation and Consequences of Ets1 Downregulation in B Cells

B 细胞中 Ets1 下调的调控和后果

• 批准号: 9896768
• 负责人: LEE ANN Garrett-Sinha
• 金额: $ 52.41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896768
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3' Untranslated Regions; Address; Affect; Alleles; Antibodies; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biological Assay; CD22 gene; CRISPR/Cas technology; Cell Nucleus; Cell Surface Receptors; Development; Discrimination; Disease; Down-Regulation; Event; Failure; Foundations; Genes; Genetic Polymorphism; Genetic Transcription; Human; Immune response; Immune system; Immunization; Inflammation; Knock-out; Lead; Light; Link; Luciferases; Lupus; MAPK8 gene; Maintenance; Mediating; Modeling; Molecular; Mus; NR0B2 gene; Pathogenicity; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Plasma Cells; Process; Production; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Reporter; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Susceptibility Gene; Symptoms; Systemic Lupus Erythematosus; Testing; Tissues; Toll-like receptors; Up-Regulation; experimental study; genome wide association study; genomic locus; immune function; insight; novel strategies; novel therapeutic intervention; pathogen; plasma cell differentiation; prevent; protein degradation; public health relevance; recruit; sialic acid binding Ig-like lectin; transcription factor; 1-Phosphatidylinositol 3-Kinase; 3' Untranslated Regions; Address; Affect; Alleles; Antibodies; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biological Assay; CD22 gene; CRISPR/Cas technology; Cell Nucleus; Cell Surface Receptors; Development; Discrimination; Disease; Down-Regulation; Event; Failure; Foundations; Genes; Genetic Polymorphism; Genetic Transcription; Human; Immune response; Immune system; Immunization; Inflammation; Knock-out; Lead; Light; Link; Luciferases; Lupus; MAPK8 gene; Maintenance; Mediating; Modeling; Molecular; Mus; NR0B2 gene; Pathogenicity; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Plasma Cells; Process; Production; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Reporter; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Susceptibility Gene; Symptoms; Systemic Lupus Erythematosus; Testing; Tissues; Toll-like receptors; Up-Regulation; experimental study; genome wide association study; genomic locus; immune function; insight; novel strategies; novel therapeutic intervention; pathogen; plasma cell differentiation; prevent; protein degradation; public health relevance; recruit; sialic acid binding Ig-like lectin; transcription factor

 DESCRIPTION (provided by applicant): B cells can be activated to differentiate into antibody-secreting plasma cells (PCs), a process crucial for normal immune function. However, unregulated B cell differentiation can lead to the production of autoantibodies and the development of autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, B cell differentiation is under tight control. Stimulation of B cells via the B cell receptor (BCR)or Toll-like receptors (TLRs) induces activation, proliferation and differentiation by influencing the expression and activity of transcription factors in the nucleus of the B cell. Counterbalancing these activation pathways are inhibitory signaling pathways dependent on a number of cell surface receptors (for example, CD22 and Siglec-G) that are phosphorylated by the tyrosine kinase Lyn. This results in the recruitment of phosphatases such as SHP1 that reverse activation of signaling proteins in the BCR and TLR cascades. Better understanding of the negative and positive pathways controlling B cell differentiation will provide new clues into how they might be manipulated to limit B cell activation in autoimmune diseases. We have recently identified the transcription factor Ets1 to be a crucial target that is downregulated by positive BCR or TLR signaling, and whose expression is maintained by inhibitory signaling cascades. Because Ets1 blocks B cell differentiation to plasma cells, its regulation is a key event in determining the fate of B cells upon stimulation. In the absence of Ets1 or Lyn, which maintains Ets1 expression, mice accumulate plasma cells and autoantibodies. Therefore maintenance of appropriate Ets1 levels in B cells is important to prevent autoimmunity. In this proposal we will define the causes and consequences of Ets1 downregulation in B cells. In Aim 1, we will further characterize the mechanisms controlling Ets1 expression in B cells. In Aim 2, we will determine the consequences of failure to downregulate Ets1 in B cells for both humoral immune responses and the development of autoimmunity using mice in which Ets1 can be inducibly expressed in B cells. In Aim 3, we will determine whether Ets1 is similarly downregulated by activating signals in primary human B cells, whether SLE- associated Ets1 polymorphisms affect control of Ets1 expression, and whether B cells from SLE patients demonstrate reduced Ets1 expression or more efficient Ets1 downregulation. Taken together, these studies will further our understanding of the molecular mechanisms of B cell differentiation and may reveal novel therapeutic approaches for diseases such as SLE.

 描述（由适用提供）：可以激活B细胞以区分分泌抗体的浆细胞（PC），这对于正常免疫功能至关重要。然而，不受管制的B细胞分化会导致自身抗体的产生和自身免疫性疾病（如全身性红斑狼疮）（SLE）。因此，B细胞分化受到严格控制。通过B细胞受体（BCR）或TOLL样受体（TLR）刺激B细胞会影响激活，增殖和分化。 转录因子在B细胞核中的表达和活性。这些激活途径的平衡是抑制性信号传导途径取决于许多细胞表面受体（例如CD22和Siglec-G），这些受体被酪氨酸激酶Lyn磷酸化。这导致募集诸如SHP1之类的磷酸酶，从而反向BCR和TLR Cascades中信号蛋白的激活。更好地了解控制B细胞分化的负和正途径将为如何操纵它们限制自身免疫性疾病中B细胞激活的新线索。我们最近确定了转录因子ETS1是由阳性BCR或TLR信号下调的关键靶标，并且其表达通过抑制信号传导级联而维持。由于ETS1阻止了B细胞与浆细胞的分化，因此其调节是确定B细胞刺激时B细胞命运的关键事件。在没有ETS1或LYN的情况下，保持ETS1表达，小鼠会强调浆细胞和自身抗体。因此，维持B细胞中适当的ETS1水平对于防止自身免疫很重要。在此提案中，我们将定义B细胞中ETS1下调的原因和后果。在AIM 1中，我们将进一步表征控制B细胞中ETS1表达的机制。在AIM 2中，我们将确定使用均可使用小鼠在B细胞中诱导ETS1表达ETS1的鼠标免疫调查的B细胞中未下调ETS1的后果。在AIM 3中，我们将通过激活原代人B细胞中的信号来确定ETS1是否会类似地下调，SLE-1相关的ETS1多态性是否会影响对ETS1表达的控制，以及来自SLE患者的B细胞是否表现出降低的ETS 1表达或更有效的ETS1下调。综上所述，这些研究将进一步理解B细胞分化的分子机制，并可能揭示了诸如SLE等疾病的新型治疗方法。