Role of Transient Receptor Potential Vanilloid 4 (TRPV4) Calcium-permeable Channels in Fibro-inflammatory Diseases

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dc.contributor.advisorRahaman, Shaik O.en_US
dc.contributor.authorGoswami, Rishoven_US
dc.contributor.departmentNutritionen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2022-02-02T06:37:49Z
dc.date.available2022-02-02T06:37:49Z
dc.date.issued2021en_US
dc.description.abstractTissue fibrosis and foreign body response (FBR) have emerged as two major public health problems globally over the last few decades. While fibrosis is an outcome of a dysregulated wound healing process, FBR, a chronic inflammatory disease, develops when the body responds and reacts to the implantation of biological materials. Interestingly, recent studies have associated these non-specific inflammatory diseases with altering stiffness although the exact underlying mechanisms by which mechanical cues can regulate the diseases remain poorly understood. The objective of this thesis work is to determine how the changing of tissue stiffness and implant rigidity mediates disease progression of fibrosis and FBR respectively. Here we identify a novel role of a polymodal mechanosensitive calcium channel, Transient Receptor Potential Vanilloid 4 (TRPV4), as a potential cell membrane receptor/channel in the pathophysiology of FBR and skin fibrosis associated with Scleroderma, a multisystem idiopathic fibro-inflammatory connective tissue disorder. Our results showed that TRPV4 is over expressed in fibrotic skin tissue and colocalize with alpha-smooth muscle actin (a-SMA), a common myofibroblast marker. Using mouse model, we demonstrated that TRPV4 knockout mice are protected from bleomycin-induced skin fibrosis development. Additionally, in a separate mouse model, we showed that genetic ablation of the TRPV4 channel protects mice from implantation-induced macrophage foreign body giant cell (FBGC) formation, macrophage accumulation, and FBR development to biomaterials. The results of our studies also determined an essential role of TRPV4 for macrophage fusion and the mechanism by which TRPV4 and matrix stiffness leads to cytoskeletal remodeling through a feed-forward functional interaction generating cellular force to modulate FBGC formation. We also identified a mechanosensing domain of TRPV4 which is crucial for FBGC generation. Altogether, the results presented in this thesis suggest TRPV4 as a potential regulator of stiffness-dependent fibrosis and inflammation development, and multinucleated FBGC formation. The results of this thesis work proposes that interaction between TRPV4 and substrate stiffness leads to cytoskeletal remodeling and cellular force generation to modulate FBGC formation under FBR. Overall, the work presented in this thesis provides a better understanding about the role of mechanosensitive calcium channel TRPV4 in the regulation of fibro-inflammatory diseases and highlights the possibilities of therapeutically targeting of this channel for disease management.en_US
dc.identifierhttps://doi.org/10.13016/kavh-4vkd
dc.identifier.urihttp://hdl.handle.net/1903/28365
dc.language.isoenen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pqcontrolledBiochemistryen_US
dc.subject.pqcontrolledMolecular biologyen_US
dc.subject.pquncontrolledFibrosisen_US
dc.subject.pquncontrolledForeign Body Giant Cellen_US
dc.subject.pquncontrolledForeign Body Responseen_US
dc.subject.pquncontrolledMechanosensingen_US
dc.subject.pquncontrolledSystemic Sclerodermaen_US
dc.subject.pquncontrolledTransient Receptor Potential Vanilloid 4en_US
dc.titleRole of Transient Receptor Potential Vanilloid 4 (TRPV4) Calcium-permeable Channels in Fibro-inflammatory Diseasesen_US
dc.typeDissertationen_US

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