Nutrition & Food Science
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Item Role of Transient Receptor Potential Vanilloid 4 (TRPV4) Calcium-permeable Channels in Fibro-inflammatory Diseases(2021) Goswami, Rishov; Rahaman, Shaik O.; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Tissue 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.Item Identification and functional analysis of a biflavone as a novel inhibitor of TRPV4-dependent atherogenic process in macrophages(2021) Alharbi, Mazen Obaid; Rahaman, Shaik O.; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular disease is the major cause of death throughout the world. Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity throughout the world. During early atherogenesis, as a result of inflammation and endothelial dysfunction, monocytes transmigrate into the aortic intimal areas, and differentiate into lipid-laden macrophage foam cells, a critical process in atherosclerosis. Numerous natural compounds such as flavonoids and polyphenols are known to have anti-inflammatory and anti-atherogenic properties. Transient receptor potential vanilloid 4 (TRPV4), a non-selective Ca2+-permeant ion channel and a mechanosensor, is widely expressed in diverse cell types including macrophages. Accumulating reports from our laboratory and others on TRPV4 recognized this plasma membrane receptor/channel as an essential modulator of various physiological functions in cardiac, pulmonary, urinary, skeletal, digestive system, and central and peripheral nervous systems. Thus, it is expected that aberrant regulation of TRPV4 activity may lead to multiple pathological conditions such as cardiovascular disease, pulmonary disease, inflammation, neurological disorders, inflammatory bowel disease and wound healing. Previous studies by our group and others have reported that TRPV4 can be activated by numerous mechanical and biochemical stimuli including shear stress, osmolarity, temperature, and growth factors, as well as by alterations in matrix stiffness in vitro and in vivo. Recently, we reported that oxidized low-density lipoprotein-mediated and matrix stiffness-induced macrophage foam cell formation, a critical pathological process in atherosclerosis, is regulated in a TRPV4-dependent manner. Given that TRPV4 is a mechanosensitive channels and mechanical factors like hypertension, disrupted laminar flow of blood, and matrix stiffening are recognized pro-atherogenic factors, makes TRPV4 an important target for therapeutic intervention of atherosclerosis. The objectives of this proposal is to: i) identify natural inhibitor (s) of TRPV4 utilizing a fluorometric imaging plate reader-supported Ca2+ influx assay, ii) functionally characterize the identified compound, and iii) determine the mechanisms by which the identified compound blocks pro-atherogenic/inflammatory TRPV4 activity in macrophages. We expect that the results of this study may strengthen the rationale for the use of natural compounds for developing therapeutic and/or chemopreventive molecules.Item TRPV4, a calcium-permeable channel, regulates oxidized LDL-induced macrophage foam cell formation(2017) Goswami, Rishov; Rahaman, Shaik O.; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Accumulation of lipid-laden “macrophage foam cell” in the arterial wall is the hallmark of atherosclerosis that leads to the highest number of cardiovascular disease-related deaths in United States. Membrane scavenger receptors such as SR-A, and CD36 play important role in controlling oxidized low-density lipoprotein binding and uptake, and, thereby, in macrophage foam cell formation. Recent studies also put emphasis on the role of mechanical factors, such as matrix stiffness, in the regulation of macrophage function and atherogenesis. However, the identity of a plasma membrane mechanosensor and the underlying mechanisms that may promote atherogenesis is yet to be identified. We have found that a calcium-permeable plasma membrane protein TRPV4, a mechanosensor, may play an essential role in regulating macrophage foam cell formation, a critical process in atherosclerosis. We have also found that TRPV4 is essential for oxLDL uptake, but not for its binding. Altogether, herein, we demonstrate that TRPV4 plays a critical role in macrophage-foam-cell formation by regulating oxLDL uptake in cells.