Monday, November 25, 2024
11/25/2024
Project Summary The 70-kilodalton heat shock protein (HSP70) family, universally conserved across prokaryotic and eukaryotic organisms, serves as essential molecular chaperones for maintaining protein homeostasis. They are central to the pathology of various diseases, including cancer, infectious diseases, neurodegeneration, and cardiovascular disorders. Beyond their established intracellular roles, HSP70 proteins also manifest in the extracellular space, significantly influencing cancer biology by modulating immune responses and facilitating metastasis. This positions them as vital biomarkers for deciphering and potentially targeting the mechanisms underlying cancer pathology. The critical involvement of HSP70 in such diverse human pathologies underscores the potential of therapeutic strategies to modulate HSP70 pathways. Delving into the complex structure-function relationship of HSP70 is essential for developing novel therapeutic interventions capable of addressing various pathologies. This project aims to elucidate the intricate roles of the cytosolic HSP70, with a particular emphasis on its underexplored structural attributes and their ramifications for cellular operations and disease pathogenesis. The long-term objectives include a deeper understanding of HSP70’s role in maintaining cellular integrity and stress response, which is crucial for developing innovative therapeutic interventions for various diseases. Specifically, the research will concentrate on HSP70’s lectin-like capacity to bind O-GlcNAcylated proteins, its ability to bind calcium/calmodulin, and its extracellular functions. These functionalities are hypothesized to be pivotal in modulating cellular thermoresistance and stress responses and potentially influencing the onset and progression of various diseases. The chosen model system for this investigation is Arabidopsis cytosolic HSP70 (AtHSP70), selected for its significant homology to human HSP70 isoforms and its established role in conferring heat stress resilience in plants. This model provides a robust framework for dissecting the conserved mechanisms of HSP70 function relevant to human health, thus directly aligning with the mission of improving the understanding and treatment of human diseases. To achieve these aims, the project will employ cutting-edge techniques such as proximity labeling with TurboID to identify novel protein interactions in vivo and lectin weak affinity chromatography to characterize the interaction between HSP70 and glycosylated proteins. Through a detailed examination of these interactions, the project seeks to expand the current understanding of HSP70’s intracellular and extracellular functions and uncover potential therapeutic targets within the HSP70 pathway. By revealing how alterations in HSP70’s interactions with carbohydrates and Ca2+/CaM can influence disease mechanisms, the research aims to open new avenues for developing therapies that modulate these pathways. In essence, this project embodies a strategic approach to bridging fundamental biological research with potential clinical applications, thereby underscoring its relevance to the overarching goal of advancing human health by targeting the molecular bases of disease.
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