Proteostasis regulators in blood cell development and function

在成年哺乳动物中，所有的血细胞都来自骨髓造血干细胞(HSCs)，通过一个严格调控的发育过程，HSCs通过祖细胞逐步分化，最终形成各种终末分化的血细胞谱系。在这一发育过程和整个生命周期中，血细胞不断地将细胞外和细胞内的信号(如细胞因子、抗原受体和代谢物)整合到一个细胞和分子程序中，该程序在促进细胞存活的同时印记细胞的身份和功能。虽然保持基因组完整性对血细胞发育和功能的重要性现在已经得到了充分的证实，但在分化过程中，保持蛋白质组完整性是否以及如何影响造血细胞的命运还不是很清楚。蛋白质组稳态(或“蛋白质稳态”)描述了蛋白质从翻译到最终周转的命运。在哺乳动物细胞中，这种蛋白稳定是通过胞浆或细胞器特异的未折叠蛋白反应途径的互补活动来完成的，这些反应途径在胞浆或粗面内质网中翻译后，监测和促进蛋白质折叠和介导蛋白质降解的泛素蛋白酶体系统。我的研究目标是了解血细胞中蛋白平衡的机制，以及蛋白平衡途径如何促进正常和恶性血细胞的发育和功能。我们的中心假设是，蛋白平衡途径决定了血细胞分化的结果，蛋白平衡机制的衰退或缺陷导致了造血细胞功能障碍和恶性肿瘤。为此，我们利用基因组学、转录组学和蛋白质组学中最先进的工具，在相关的人类样本和动物模型中评估蛋白稳定途径的变化如何影响正常的血细胞发育和疾病发病机制。从长远来看，我们预计这些研究将揭示蛋白平衡途径中的脆弱性，可用于增强造血、改善免疫细胞功能和治疗血癌。结合相关的人类样本和创新的小鼠遗传模型，我们目前对这一假说的研究主要集中在三个方面：1.未折叠蛋白反应(UPR)在HSC维持和恶性中的作用。2.UPR缺陷在T细胞功能障碍中的作用3.适配蛋白CHMP5对正常和恶性造血细胞的调节

In adult mammals, all blood cells arise from bone marrow hematopoietic stem cells (HSCs) through a tightly regulated developmental process involving progressive differentiation of HSCs through progenitor cells and culminating in various terminally differentiated blood cell lineages. During this developmental process and throughout their lifespan, blood cells continually integrate both extracellular and cell intrinsic signals (e.g., cytokines, antigen receptors and metabolites) into a cellular and molecular program that imprints cell identity and function while promoting their survival. While the importance of maintaining genome integrity to blood cell development and function is now well-established, it is less clear if and how maintenance of proteome integrity impacts hematopoietic cell fate during differentiation. Proteome homeostasis (or "proteostasis") describes the fate of proteins from translation to their eventual turnover. In mammalian cells, this proteostasis is accomplished by the complimentary activity of cytosolic or organelle-specific unfolded protein response pathways that, following translation in the cytosol or rough endoplasmic reticulum, monitor and promote protein folding and the ubiquitin proteasome system that mediates protein degradation. The goal of my research is to understand mechanisms of proteostasis in blood cells and how proteostasis pathways contribute to normal and malignant blood cell development and function. Our central hypothesis is that proteostasis pathways determine blood cell differentiation outcomes and that decline or defects in the proteostasis machinery contributes to hematopoietic cell dysfunction and malignancy. To this end, we utilize state-of-the-art tools in genomics, transcriptomics, and proteomics to assess how changes in proteostasis pathways affect normal blood cell development and disease pathogenesis in relevant human samples and animal models. In the long term, we expect that these studies will uncover vulnerabilities in proteostasis pathways that can be exploited to augment hematopoiesis, improve immune cell function, and treat blood cancers. Combining relevant human samples with innovative genetic mouse models that allow precise dissection of core mammalian proteostasis pathways in vitro and in vivo, our investigation of this hypothesis is currently centered around three areas of research: 1. The unfolded protein response (UPR) in HSC maintenance and malignancy. 2. The role of UPR deficiency in T cell dysfunction 3. Tunable regulation of normal and malignant hematopoietic cells by the adaptor protein CHMP5