Understanding the mechanisms of immune receptor signalling and how to target this process in disease

了解免疫受体信号传导机制以及如何针对疾病中的这一过程

• 批准号: 2897399
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2897399
• 关键词: Understanding; mechanisms; immune; receptor; signalling

B lymphocytes play a crucial role in adaptive immunity, being responsible for antibody production as well as contributing to antigen presentation and cytokine secretion to coordinate the immune response. Stimulation of B cells occurs primarily through the B-cell receptor (BCR), a surface-exposed membrane-integrated immunoglobulin. Antigen binding to the BCR stimulates a number of downstream signalling pathways that control B-cell differentiation, proliferation and migration. Dysregulation of BCR signalling is responsible for human malignancies such as lymphoid leukaemia and lymphoma and is also associated with various immunological disorders. Because of its crucial importance in B cell physiology, the BCR has been intensively investigated for many years. In our recent work, we have uncovered a novel mechanism controlling BCR clustering and signalling, which involves the inositol phosphatase INPP5B. Preliminary results also suggest INPP5B is important for B cell physiology and the proliferation of lymphoma cells. The goal of this project is to build upon our work to date to decipher the molecular details of how INPP5B controls BCR dynamics, how this occurs in time and space, and to determine its significance for normal B cell functions as well as those occurring in cancerous B cells. The project will involve cell biology and immunological techniques, which will include proteomics, high-end live and fixed cell imaging, combined with immune phenotyping, cancer cell proliferation and migration assays. The findings will provide major new insights into the BCR and will have significant implications for our understanding of the healthy immune system, as well as B cell disorders such as leukaemia and lymphoma.

B淋巴细胞在适应性免疫中起着至关重要的作用，负责抗体产生，并有助于抗原表现和细胞因子分泌以协调免疫反应。 B细胞的刺激主要通过B细胞受体（BCR）（一种表面暴露的膜积分的免疫球蛋白）发生。抗原与BCR的结合刺激了控制B细胞分化，增殖和迁移的许多下游信号通路。 BCR信号的失调导致人类恶性肿瘤（如淋巴样白血病和淋巴瘤），也与各种免疫疾病有关。由于其在B细胞生理学中的重要性至关重要，因此BCR已进行了多年的深入研究。在最近的工作中，我们发现了一种控制BCR聚类和信号传导的新型机制，该机制涉及肌醇磷酸酶INPP5B。初步结果还表明，INPP5B对于B细胞生理和淋巴瘤细胞的增殖很重要。该项目的目的是建立我们迄今为止的工作，以破译INPP5B如何控制BCR动力学，如何在时间和空间中发生的分子细节，并确定其对正常B细胞​​功能以及在癌症B细胞中发生的意义。该项目将涉及细胞生物学和免疫学技术，其中包括蛋白质组学，高端活细胞成像，并结合免疫表型，癌细胞增殖和迁移分析。这些发现将为BCR提供主要的新见解，并将对我们对健康免疫系统以及白血病和淋巴瘤等B细胞疾病产生重大影响。