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

B淋巴细胞在适应性免疫中起关键作用，负责抗体产生以及有助于抗原呈递和细胞因子分泌以协调免疫应答。B细胞的刺激主要通过B细胞受体（BCR）发生，BCR是一种表面暴露的膜整合免疫球蛋白。抗原与BCR的结合刺激许多控制B细胞分化、增殖和迁移的下游信号传导途径。BCR信号转导失调是人类恶性肿瘤如淋巴白血病和淋巴瘤的原因，也与各种免疫性疾病有关。由于其在B细胞生理学中的至关重要性，BCR已被深入研究多年。在我们最近的工作中，我们发现了一种控制BCR聚集和信号传导的新机制，该机制涉及肌醇磷酸酶INPP5B。初步结果还表明INPP 5 B对B细胞生理学和淋巴瘤细胞的增殖是重要的。该项目的目标是建立在我们迄今为止的工作，以破译INPP 5 B如何控制BCR动力学的分子细节，这是如何在时间和空间发生的，并确定其对正常B细胞功能的意义，以及发生在癌性B细胞。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、高端活细胞和固定细胞成像，结合免疫表型分析、癌细胞增殖和迁移分析。这些发现将为BCR提供重要的新见解，并将对我们理解健康的免疫系统以及B细胞疾病（如白血病和淋巴瘤）产生重大影响。

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.