Characterization of Twixt: a novel membrane adaptor protein in B cells

Twixt 的表征：B 细胞中的一种新型膜接头蛋白

• 批准号: 8369296
• 负责人: ROBERT C RICKERT
• 金额: $ 29.25万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369296
• 关键词: Adaptor Signaling Protein; Alleles; Antibody Formation; Antigens; Autoimmunity; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; BLNK gene; Binding; Biochemical; Brain region; CD19 gene; Cell Nucleus; Cell physiology; Complex; Data; Defect; Gene Expression; Genetic; Goals; Human; Immune Sera; Knowledge; Location; Measures; Membrane; Molecular; Mus; Nature; Pathway interactions; Peripheral; Phenotype; Phosphorylation; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Rest; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Structure of germinal center of lymph node; Tyrosine; Work; base; in vivo; insight; macrophage; memory recall; novel; receptor; recombinase; research study; response; selective expression

DESCRIPTION (provided by applicant): We recently completed the first comprehensive study of tyrosine phosphorylated substrates in resting and BCR-stimulated primary B cells. From this effort, we focused on a novel transmembrane adaptor protein, termed Twixt, due to its novelty, selective expression in B cells and potential importance in fulfilling a knowledge gap in our understanding of BCR signaling - namely how BLNK is inducibly recruited to the BCR complex. In the proposed work, we will determine how Twixt is recruited and utilized by the BCR and perhaps other receptors to effect downstream signaling. These data will provide a mechanistic framework for interpreting the phenotypes observed in Twixt-deficient mice, which will be generated and analyzed in the second Aim. Completion of the proposed studies will establish the prominence of Twixt as a central player in BCR signaling, or reveal a more selective role. PUBLIC HEALTH RELEVANCE: Signaling via the B cell antigen receptor (BCR) determines the fate of the B cell in terms of continued survival, proliferation and differentiation. These signals are relayed to the nucleus to bring about changes in gene expression that will decide B cell fate. The nature of these signals remains incomplete - as is our understanding of how aberrant signal transduction can precipitate B cell autoimmunity or transformation. In the proposed work we will characterize a novel B cell signaling adaptor that may be quite important in parsing this early membrane-proximal signal to engage downstream effector pathways.

描述（由申请人提供）：我们最近完成了对静息和BCR刺激的原代B细胞中酪氨酸磷酸化底物的首次全面研究。从这项工作中，我们专注于一种新的跨膜衔接蛋白，称为Twixt，由于其新奇，在B细胞中的选择性表达和潜在的重要性，在满足我们的理解BCR信号转导的知识差距-即如何BLNK是诱导招募到BCR复合物。在拟议的工作中，我们将确定Twixt是如何被BCR和其他受体招募和利用来影响下游信号传导的。这些数据将为解释Twixt缺陷小鼠中观察到的表型提供机制框架，这些表型将在第二个目标中生成和分析。完成拟议的研究将确立Twixt作为BCR信号传导中的核心参与者的重要性，或揭示更具选择性的作用。 公共卫生相关性：通过B细胞抗原受体（BCR）的信号传导决定了B细胞在持续存活、增殖和分化方面的命运。这些信号被传递到细胞核，引起基因表达的变化，从而决定B细胞的命运。这些信号的性质仍然是不完整的-我们的理解是如何异常的信号转导可以沉淀B细胞自身免疫或转化。在拟议的工作中，我们将描述一种新的B细胞信号转导适配器，可能是相当重要的，在解析这个早期的近膜信号，从事下游效应途径。