Proteostasis regulators in blood cell development and function

在成年哺乳动物中，所有的血细胞都是由骨髓造血干细胞（HSCs）经过一个严格调控的发育过程产生的，包括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信号（如细胞因子、抗原受体和代谢物）整合到细胞和分子程序中，从而在促进细胞存活的同时印记细胞的身份和功能。虽然维持基因组完整性对血细胞发育和功能的重要性现已得到证实，但维持蛋白质组完整性是否以及如何影响造血细胞分化过程中的命运尚不清楚。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，这种蛋白质静止是通过细胞质或细胞器特异性未折叠蛋白反应途径的互补活性来完成的，这些途径在细胞质或粗内质网翻译后，监测和促进蛋白质折叠以及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液细胞中蛋白质平衡的机制，以及蛋白质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，蛋白质平衡途径决定血细胞分化结果，蛋白质平衡机制的下降或缺陷导致造血细胞功能障碍和恶性肿瘤。为此，我们利用最先进的基因组学、转录组学和蛋白质组学工具，在相关的人类样本和动物模型中评估蛋白质平衡途径的变化如何影响正常血细胞发育和疾病发病机制。从长远来看，我们期望这些研究将揭示蛋白质停滞途径的脆弱性，从而可以用来增强造血，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遗传小鼠模型，可以精确地解剖体外和体内的核心哺乳动物蛋白酶抑制途径，我们对这一假设的研究目前主要集中在三个研究领域：1。未折叠蛋白反应（UPR）在HSC维持和恶性肿瘤中的作用。2. UPR缺乏在T细胞功能障碍中的作用受体蛋白CHMP5对正常和恶性造血细胞的可调调节

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