Description of Research
The overall focus of the laboratory of Masao Kaneki, MD, PhD, is to understand the role of inflammatory/stress signaling cascades in the molecular pathogenesis in human diseases. Inflammation is implicated in a variety of human diseases, whereas it is a necessary and adaptive response to environmental or intrinsic stress. Thus, inflammation functions as a double-edged sword, and hence its activation needs to be tightly regulated.
Nonetheless, how inflammatory response is regulated or when it becomes pathogenic is not well understood. In this context, the major questions my research team has been trying to address include:
We focus on cysteine thiol modifications, protein S-nitrosylation (the covalent attachment of nitric oxide to thiols) and farnresylation, as potential hubs of the nexus of positive feed-forward signaling networks that forms the inflammatory Warburg-like metabolic shift complex.
Project 1 is to clarify how inducible nitric oxide synthase (iNOS), a major mediator of inflammation, causes or exacerbates obesity- and stress (e.g., burn)-induced insulin resistance and pancreatic β-cell dysfunction.
My research team has established the role of iNOS in obesity- and stress-induced insulin resistance. iNOS-mediated S-nitrosylation of Akt inactivates it (Akt is a key player in the metabolic actions of insulin [e.g., glucose uptake]).
In addition, iNOS decreases insulin receptor substrate (IRS)-1 and IRS-2 expression in skeletal muscle and liver in obese, diabetic mice and burned mice and in pancreatic β-cells.
The Kaneki laboratory has been the frontrunner on the role of iNOS in obesity- and burn-induced insulin resistance.
In Project 2, the research in my laboratory has identified “inducible farnesylation” as a key component of inflammatory spiral and the Warburg-like metabolic shift.
The cholesterol-lowering independent pleiotropic beneficial effects of statins, inhibitors of HMG-CoA reductase, have attracted much scientific attention since the 1990s.
Dr. Kaneki posits that inhibition of farnesylation is a major mechanism of the pleiotropic beneficial effects of statins. His research team has shown that farnesyltransferase inhibitors (FTIs) improve the survival in murine models of endotoxemia, sepsis and acute fulminant hepatitis, and prevents atherogenesis in ApoE knockout mice and burn-induced insulin resistance in mice.
Moreover, he proposes the new concept of “inducible farnesylation,” where inflammation or stress induces de novo farnesylatoin in proteins that are not farnesylated or farnesylated to a small extent under basal conditions. This project is expected to aid the development of clinical trials of FTIs in inflammatory diseases, including critical illness (e.g., sepsis, burn).
In Project 3, the Kaneki Lab is investigating the mechanisms of inflammatory spiral common to aging-related disorders. In aging-related disorders, including diabetes, aging-associated pneumonia and neurodegeneration, inflammation and cell death play crucial roles in the pathogenesis. Nonetheless, some important questions remain to be addressed.
The first such question is whether there are exist mechanisms common to the pathogenesis of a variety of aging-related disorders.
In a recent study, we have shown that iNOS-dependent S-nitrosylation of the Cys-X-X-Cys motifs in SIRT1, a NAD+-dependent deacetylase, inactivates SIRT1, and thereby increases acetylation and activity of p53 and p65 NF-κB in rodent models of sarcopenia, Parkinson’s disease and systemic inflammatory response syndrome.
Collectively, our study indicates that SIRT1 S-nitrosylation function as a pro-inflammatory switch that initiates and sustains the inflammatory spiral consisting of the iNOS→SIRT1 S-nitrosylation→activation of p53 and p65 NF-κB→iNOS.
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