Birc5 as a regulator of NK cell development and immune function

Birc5 作为 NK 细胞发育和免疫功能的调节剂

• 批准号: 10066361
• 负责人: Aimee Melissa Beaulieu
• 金额: $ 38.96万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066361
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Anti-Inflammatory Agents; Antiviral Agents; BIRC5 gene; Bone Marrow; Cell Line; Cell Nucleus; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Cellular biology; Cellular immunotherapy; Clinic; Clinical; Clinical Trials; Cues; Cytoplasm; Data; Development; Environment; FRAP1 gene; Family member; Future; Generations; Genetic Techniques; Goals; Growth; Growth Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunotherapeutic agent; Impairment; In Vitro; Infection; Inflammatory; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Investigation; Longevity; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolism; Mitochondria; Mitosis; Molecular; Molecular Genetics; Mus; Natural Killer Cells; Pathway interactions; Peripheral; Pharmacology; Population; Process; Production; Property; Regimen; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transforming Growth Factor beta; Transgenic Mice; Virus; Virus Diseases; Xenograft Model; base; cancer cell; cancer therapy; cytokine; experimental study; extracellular; gain of function; immune function; in vivo; infection related cancer; inhibitor-of-apoptosis protein; innovation; novel; overexpression; pathogen; pathogenic virus; progenitor; sensor; single-cell RNA sequencing; stem; stem cells; tumor

ABSTRACT Natural Killer (NK) cells are cytotoxic lymphocytes that mediate immune defense against viral pathogens and tumors. In clincial settings, NK cells are being targeted in adoptive cell transfer (ACT) and hematopoietic stem cell transplantation (HSCT) regimens, and immunotherapeutic approaches, to treat cancer and cancer-related infections. Effective NK cell immunity is predicated on the sustained presence of a pool of functional NK cells in the periphery. At steady state, the NK cell niche is maintained by the continual development of new NK cells from progenitor populations in the bone marrow and by the homeostatic expansion of mature NK cells in the periphery. In addition, certain inflammatory signals may transiently expand effector NK cells needed for protection during infection or malignancy. Understanding the molecular pathways that control these processes will critically impact the development of novel and more effective NK cell-based therapies in the clinic. Our preliminary studies have highlighted a critical role for the Inhibitor of Apoptosis Protein (IAP), Birc5, in NK cell hematopoiesis and function. Prior studies in stem cells and cancer cells have shown that Birc5 contributes to a broad range of cellular functions, including mitosis, survival, and cellular metabolism, acting through its highly compartmentalized activities in the nucleus, cytoplasm, and mitochondria, respectively. A role for Birc5 in NK cell biology has not been described. New data in our lab indicate that Birc5 is highly and transiently upregulated in NK cells undergoing expansion in the context of development in the bone marrow, or viral infection in the periphery. Further, our preliminary studies indicate that Birc5-deficiency severely impairs mouse NK cell development and maturation. The specific cellular functions of Birc5 in NK cells, as well as its roles in homeostatic- and infection-related NK cell expansion remain to be defined. Thus, we will conduct studies that test the central hypothesis that Birc5 acts downstream of key cytokine and metabolic growth signals to orchestrate NK cell expansion during development and peripheral immunity. These studies will utilize novel transgenic mice, in which the Birc5 gene can be deleted in NK cells in a cell-specific or conditional manner, to investigate the contributions of Birc5 to NK cell proliferation, survival, and metabolic function in settings of development, homeostatic expansion, and anti-viral immune responses in vivo. Further, we will combine sophisticated molecular and genetic techniques to define the environmental cues and intracellular signaling networks that modulate Birc5 function in NK cells. And finally, we will use an innovative mouse xenograft model to study Birc5 function in human NK cells in vivo. Ultimately, our studies have the potential to inform ongoing and future NK cell-based immunotherapies, including adoptive cell transfer (ACT) and hematopoietic stem cell transfer (HSCT) regimens that harness the anti-tumor properties of NK cells to treat cancer. !

抽象的 天然杀伤（NK）细胞是细胞毒性淋巴细胞，可介导对病毒病原体的免疫防御和 肿瘤。在边缘设置中，NK细胞针对收养细胞转移（ACT）和造血茎 细胞移植（HSCT）方案和免疫治疗方法，以治疗癌症和癌症有关 感染。有效的NK细胞免疫是基于持续存在功能性NK细胞库 外围。在稳定状态下，NK细胞小众通过新NK细胞的持续发展维持 来自骨髓中的祖细胞和通过成熟NK细胞的稳态扩张 周边。另外，某些炎症信号可能会瞬时扩展效应子NK细胞 感染或恶性肿瘤的保护。了解控制这些过程的分子途径 将严重影响诊所中新型和更有效的NK细胞疗法的发展。 我们的初步研究强调了凋亡蛋白抑制剂（IAP），BIRC5，，， 在NK细胞造血和功能中。先前在干细胞和癌细胞的研究表明BIRC5 促进广泛的细胞功能，包括有丝分裂，生存和细胞代谢，作用 分别通过其在细胞核，细胞质和线粒体中的高度分室活性。一个 BIRC5在NK细胞生物学中的作用尚未描述。我们实验室中的新数据表明BIRC5高度高 在骨髓发育的情况下，在NK细胞中瞬时上调 外围病毒感染。此外，我们的初步研究表明，BIRC5缺乏严重损害 小鼠NK细胞的发育和成熟。 NK细胞中BIRC5的特定细胞函数及其 在体内和感染相关的NK细胞扩展中的作用仍有待定义。因此，我们将进行 测试中心假设的研究，即BIRC5在关键细胞因子和代谢生长的下游作用 在发育和外周免疫期间编排NK细胞扩展的信号。这些研究将利用 新型转基因小鼠，其中BIRC5基因可以在细胞特异性或条件的NK细胞中删除 方式，研究BIRC5对NK细胞增殖，存活和代谢功能的贡献 在体内发育，稳态扩张和抗病毒免疫反应的设置。此外，我们会的 结合精致的分子和遗传技术来定义环境线索和细胞内 调节BIRC5在NK细胞中功能的信号网络。最后，我们将使用创新的鼠标 异种移植模型在体内研究BIRC5在人NK细胞中的功能。最终，我们的研究有可能 告知正在进行的和未来的基于NK细胞的免疫疗法，包括收养细胞转移（ACT）和 造血干细胞转移（HSCT）方案，该方案利用NK细胞的抗肿瘤特性治疗 癌症。 呢