Strawberry notch homologues in T cell homeostasis and function

T 细胞稳态和功能中的草莓缺口同源物

• 批准号: 10219905
• 负责人: XIAOPING ZHONG
• 金额: $ 56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-21 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219905
• 关键词: Ablation; Adult; Affect; Antibodies; Antibody Response; Antigens; Antiviral Agents; B cell differentiation; B-Cell Development; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Survival; Cell physiology; Cellular biology; Cessation of life; Child; Collaborations; Common Variable Immunodeficiency; Data; Development; Disease; Drosophila genus; Embryonic Development; Exons; Eye Development; Family; Gene Expression; Genes; Genetic Transcription; Homeostasis; Homologous Gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Impairment; Infection; Knockout Mice; Leg; LoxP-flanked allele; Mammals; Mediating; Memory; Missense Mutation; Mus; Mutation; Nuclear Proteins; Oogenesis; Pathogenesis; Pathway interactions; Patients; Physiological; Proteins; RNA Helicase; Reactive Oxygen Species; Recurrence; Regulation; Role; Shapes; Strawberries; Structure; Structure of germinal center of lymph node; T-Cell Development; T-Lymphocyte; Therapeutic; Thymus Gland; Vaccination; Virus Diseases; Wing; cell mediated immune response; conditional knockout; immunoregulation; improved; insight; microbial; mouse model; notch protein; novel; novel therapeutic intervention; prevent; prophylactic; response; virtual; whole genome

Abstract Effective and long lasting antibody responses, which require delicate collaboration from both T and B cells, is essential for immune responses to antigens and successful vaccinations against microbial infections; however, the mechanisms that regulate T cell function in antibody responses are still not fully understood. In addition, hypogammaglobinemia is the hallmark of common variable immunodeficiency (CVID), which can result in repetitive infections and even death of children and is the most common symptomatic primary immune deficiency in adults with causal factors in most patients still elusive. Via whole genome exon sequencing, we have identified a mis-sense mutation in the Strawberry Notch homologue 2 (SBNO2) gene. SBNO1/2 are conserved nuclear proteins belonging to the DExD/H RNA helicase family. Their orthologue, strawberry notch (SNO), functions downstream of Notch/Hippo pathways and is important for embryogenesis, oogenesis, and development of the eye, wing and leg in drosophila. However, the functions of SBNO1/2 in mammals, especially in the immune system, and whether these two proteins perform overlapping functions are virtually unknown. We have generated a novel mouse model, Sbno2m/m, that harbors a CVID mutation in the endogenous Sbno2 gene and conditional Sbno1 and Sbno2 deficient mice. With strong preliminary data from these mice, we hypothesize that Sbno1/2 are critical players in T cells for their development and function, particularly in T cell-mediated antibody and anti-viral immune responses. We will 1) determine the roles of Sbno1 and Sbno2 for T cell development and homeostasis, 2) determine the role of Sbno1 and Sbno2 in T cell mediated immune responses, and 3) investigate the mechanisms underlying Sbno1/2- mediated immune regulation. The proposed studies are expected to illustrate novel mechanisms that control T cell development, homeostasis, and function to shape antibody and anti-viral immune responses. By illustrating the importance of Sbno1/2 in T cells, we will provide insight into mechanisms underlying T cell biology and CVID that will guide the development of novel therapeutic strategies against immune-related disorders.

摘要 有效和持久的抗体应答需要T细胞和B细胞的微妙合作， 对抗原的免疫反应和成功接种抗微生物感染的疫苗至关重要; 然而，在抗体应答中调节T细胞功能的机制仍不完全清楚。在 此外，低丙种球蛋白血症是常见变异型免疫缺陷（CVID）的标志， 导致反复感染，甚至儿童死亡，是最常见的症状性原发性 成人免疫缺陷与大多数患者的致病因素仍然难以捉摸。通过全基因组外显子 测序，我们已经确定了草莓Notch同源物2（SBNO 2）基因的错义突变。 SBNO 1/2是属于DExD/H RNA解旋酶家族的保守核蛋白。他们的直系同源物， 草莓切口（SNO），在Notch/Hippo途径的下游起作用，对胚胎发生很重要， 卵子发生，以及果蝇眼睛、翅膀和腿的发育。然而，SBNO 1/2在 哺乳动物，尤其是免疫系统，以及这两种蛋白质是否具有重叠的功能 几乎无人知晓我们已经产生了一种新的小鼠模型，Sbno 2 m/m，其在小鼠中携带CVID突变。 内源性Sbno 2基因和条件性Sbno 1和Sbno 2缺陷小鼠。有了强有力的初步数据 从这些小鼠中，我们假设Sbno 1/2是T细胞发育的关键参与者， 功能，特别是在T细胞介导的抗体和抗病毒免疫应答中。我们将1）确定 Sbno 1和Sbno 2对T细胞发育和稳态的作用，2）确定Sbno 1和Sbno 2的作用， Sbno 2在T细胞介导的免疫应答中的作用，以及3）研究Sbno 1/2- 介导的免疫调节。预计拟议的研究将阐明控制 T细胞发育、稳态和功能，以形成抗体和抗病毒免疫应答。通过 通过阐明Sbno 1/2在T细胞中的重要性，我们将深入了解T细胞的潜在机制。 生物学和CVID，将指导新的治疗策略的发展，对免疫相关的 紊乱