Elucidating the secretion proteome of human


18-Dec-2016 19:10

We are exploring the functional impact of UPR-dependent remodeling of ER proteostasis pathways using genetically-encoded, ligand-regulated constructs of UPR-associated transcription factors such as XBP1s and ATF6 in combination with transcriptional profiling and quantitative proteomic experimental techniques.Through these efforts, we are characterizing in molecular detail the impact of UPR activation on the composition of ER proteostasis pathways and elucidating the therapeutic potential for selective activation of UPR-associated transcription factors to selectively alter the aberrant ER folding, trafficking or degradation of destabilized protein variants associated with numerous human protein misfolding diseases.Label-free quantification demonstrated mineralization stage-dependent 5-fold enrichment of 59 and 451 EV proteins in NMOBs and MOBs, respectively. Proteomic signatures of extracellular vesicles secreted by nonmineralizing and mineralizing human osteoblasts and stimulation of tumor cell growth.Interestingly, bioinformatic analyses of the osteoblast EV proteomes and EV-regulated prostate cancer gene expression profiles showed that they converged on pathways involved in cell survival and growth. Moreover, we showed that Cyr61 is present in the culture medium (secretome) of MSCs.The secretome of MSCs stimulates angiogenic response in vitro, and neovascularization in vivo.It is well known that bone marrow-derived mesenchymal stem cells (MSCs) are involved in wound healing and regeneration responses.

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Extracellular vesicles (EVs) have been implicated in intercellular communication transfer of proteins and nucleic acids between cells.

The misfolding and aggregation of proteins in the extracellular space is inextricably linked with the onset and pathology of numerous human degenerative diseases.

The importance of extracellular protein aggregation in disease pathology has stimulated significant experimental effort focused on elucidating the cellular pathways that regulate proteostasis in the extracellular environment.

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This was verified by proliferation assays where osteoblast EV uptake led to 2-fold increase in PC3 cell growth compared to cell-free culture medium–derived vesicle controls.