Proteostasis regulators in blood cell development and function

血细胞发育和功能中的蛋白质稳态调节剂

• 批准号: 10926532
• 负责人: Stanley Adoro
• 金额: $ 92.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926532
• 关键词: Adaptor Signaling Protein; Adult; Affect; Age; Animal Model; Antigen Receptors; Area; Blood Cells; Bone Marrow; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Cytosol; Defect; Development; Developmental Process; Disease; Dissection; Functional disorder; Genetic; Genomics; Goals; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; Immune; Impairment; In Vitro; Investigation; Longevity; Macrophage; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Molecular; Monitor; Organelles; Outcome; Pathogenesis; Pathway interactions; Proteins; Proteome; Proteomics; Regulation; Research; Role; Rough endoplasmic reticulum; Sampling; Signal Transduction; System; T-Lymphocyte; Testing; Tissues; Translations; Ubiquitin; Work; cytokine; extracellular; genome integrity; hematopoietic differentiation; imprint; improved; in vivo; innovation; mouse model; multicatalytic endopeptidase complex; programs; protein degradation; protein folding; proteostasis; response; stem cells; tool; transcriptomics

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

在成年哺乳动物中，所有的血细胞都来自骨髓造血干细胞（HSC），通过严格调控的发育过程，包括HSC通过祖细胞的渐进分化，并最终形成各种终末分化的血细胞谱系。在此发育过程中以及在其整个寿命期间，血细胞不断整合细胞外和细胞内在信号（例如，细胞因子、抗原受体和代谢物）转化为细胞和分子程序，该程序在促进细胞存活的同时印记细胞身份和功能。虽然维持基因组完整性对血细胞发育和功能的重要性现在已经得到了很好的确立，但蛋白质组完整性的维持是否以及如何影响造血细胞在分化期间的命运还不太清楚。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，这种蛋白质稳态是通过胞质或细胞器特异性未折叠蛋白质反应途径的互补活性来实现的，所述未折叠蛋白质反应途径在胞质或粗面内质网中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细胞中蛋白质稳态的机制以及蛋白质稳态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，蛋白质稳态途径决定血细胞分化的结果和蛋白质稳态机制的下降或缺陷有助于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来评估蛋白质稳态途径的变化如何影响相关人类样本和动物模型中的正常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质稳态途径的漏洞，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与创新的遗传小鼠模型，允许在体外和体内精确解剖核心哺乳动物蛋白质稳态途径，我们对这一假设的研究目前集中在三个研究领域：1。未折叠蛋白反应（UPR）在HSC维持和恶性中的作用2. UPR缺陷在T细胞功能障碍中的作用3.接头蛋白CHMP5对正常和恶性造血细胞的可调调节