Proteostasis regulators in blood cell development and function

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

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