Toda Gotaro, MD, PhD | The University of Tokyo
Competition Sponsor: Japan Agency for Medical Research and Development
Awardee Year: 2024
Obesity is a major risk for the development of diabetes, kidney and heart disease, and musculoskeletal disorders, each of which diminishes quality of life. Although inflammation has been extensively reported in the development of obesity, immune cells have also been shown to sustain normal metabolic function, such as energy production and storage, and maintaining normal body weight, which are dysregulated in obesity. These normal processes are diminished in age related inflammatory states (referred to as “inflammaging”) as well. We have previously reported that production of the cytokine IL-10 is dysregulated in obesity, resulting in aggravated gluconeogenesis and elevated glucose levels after eating （Toda G et al. Mol Cell. 2020）. This project aims to identify potential pathways that maintain the normal function of immune cells, and to engineer obesity-resistant immune cells from peripheral blood that can be returned to the blood flow to improve pathological changes in obesity. We will search for target factors among genes that are increased/decreased by short-chain fatty acids (SCFAs), which have been shown to protect against obesity. We will merge spatial transcriptomics data of adipose and renal tissue from patients with or without obesity to identify targets with clinical potential, focusing on protein degradation, which was heightened under SCFA treatment in preliminary experiments. mRNA therapeutics will be key in introducing the relevant factor and in collecting cells that have obesity-resistance. We hope cell-based methods to maintain normal immune function may in the future be utilized in other immune dysregulating conditions, including age related disorders.