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Regulation of proteostasis in pluripotent stem cells by the co-chaperone STIP1


Pluripotent cells have the potential to differentiate into all cell types of an organism and understanding the mechanisms that govern pluripotency status is crucial for regenerative medicine. Evidence indicates the involvement of the proteostasis machinery, regulated by the heat shock organizing protein/stress inducible protein 1 (STIP1) and its ligands, Hsp70 and Hsp90, in embryogenesis and maintenance of embryonic stem cells (ESCs) pluripotency. Exciting results from a research project, initiated in a sabbatical period of Dr. Lopes at the University of Western Ontario, demonstrate the ability of STIP1 in the regulation of key pluripotency factors in stem cells. Based on these preliminary results, a critical component for these collaborative efforts is the generation of several mouse models targeting the STIP1 gene. Dr. Prado's group pioneered the study of the function of STIP1 in embryogenesis of mammals in vivo. Moreover, his group recently demonstrated that the deletion of STIPI in mice is embryonic lethal which suggests that STIP1 is an essential factor in the early embryonic development stage. Several STIP1 mouse lines, expressing different levels of STIP1, are available and researchers at Western are the only group in the world to maintain the newly generated STIP1”TPR1 lineage (expressing STIP1 truncated isoform). These transgenic animal strains are fundamental for our proposal to understand how STIP1 and its partners regulate proteostasis in pluripotent stem cells. We hypothesized that STIP1 is a key regulator of Hsp90 and Hsp70 chaperone machinery during development to support self-renewal and differentiation of ESCs. Our overarching aims are: i) to determine whether STIP1 regulates the levels of clients and co-chaperones required for embryonic development; ii) To determine if changes in STIP1 levels regulate self-renewal and pluripotency of ESCs; iii) To determine mechanisms by which increased and/or decreased STIP1 levels regulate embryonic stem cell resilience. To address these issues ESCs, derived from transgenic mice blastocysts expressing different STIP1 levels, will be used for cell proliferation, differentiation, survival, self-renewal, and embryoid bodies formation assays. This collaboration will allow Dr. Lopes to continue to benefit from participating in a research environment with a consolidated research group that will contribute to establishing new collaborations with potential impact on Graduate Programs for both Institutions, with short training visits of young students and fellows to both research centers to develop advanced research. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LIN, LILIAN TSAI-WEI; RAZZAQ, ABDUL; DI GREGORIO, SONJA E.; HONG, SOOJIE; CHARLES, BRENDAN; LOPES, MARILENE H.; BERALDO, FLAVIO; PRADO, VANIA F.; PRADO, MARCO A. M.; DUENNWALD, MARTIN L.. Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity. FASEB JOURNAL, v. 35, n. 5, . (19/00341-9, 16/00440-9)

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