CAREER: Probing Mechanisms of Beta Cell Dysfunction via Quantitative Droplet Molecular Transport

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

In diabetes, insulin secretion is impaired in specialized cells (called beta cells) in the pancreas, and this impairment may be related to chemical factors in the local environment around the beta cells. Of particular importance are two common risk factors of diabetes: a fatty diet (fatty acids) and lack of sufficient oxygen. In this project, a novel miniaturized pump will precisely control the beta cells' local environment so that the mechanisms of diabetes can be studied quantitatively and precisely. Results of the research will transform understanding of how diabetes develops and may explain why not all obese patients develop diabetes despite similar risk factors. These novel and transformative biomedical science and engineering investigations (or experiments) will be conducted by a team of interdisciplinary, peer-learning students, under the guidance of the principle investigator. Research is also interwoven with education, where students from graduate, undergraduate, local high school, and elementary school all participate in the experimental, interpretive, and peer-teaching aspects of the project. The proposal focuses on probing mechanisms of beta cell dysfunction, a hallmark of diabetes, through studies performed in a highly integrated platform termed "quantitative droplet molecular transport (qDMT)" based on the PI's "smart microgel" droplets and a novel microfluidic Tesla pump. The two mechanisms for initial study are 1) enhanced immunogenicity as a result of neoantigen binding to free fatty acid (FFA) exposed beta cells and 2) beta cell impairment as a result of a potential synergy between FFA and hypoxia in modulating adipocyte cytokines. The qDMT is a unique tool for quantifying protein transport in situ due to three novel features:: 1) Smart microgels allow antibody binding to be assayed while modifying the antigens in situ, i.e., within the porous droplets, bead biosensors can be placed right next to cells of interest so the diffusion length is dramatically shortened, accelerating sensitive protein detection in situ; 2) The miniaturizing bladeless Tesla pump optimizes use of boundary layers, enabling a completely sealed, continuous flow difficult to achieve with conventional pumps and 3) Microchannel dimensions can be varied to create predictable diffusion models to quantify molecular kinetics. The Research Plan is organized around three objectives: 1) Engineer qDMT with cell & biosensor laden smart microgels, a micro-Tesla pump and reconfigurable microfluidics. 2) Apply qDMT to study neoantigen (insulin, GAD, IA-2, ZnT8) binding in FFA exposed beta cells and 3) Apply qDMT to study FFA+hypoxia synergy in adipocyte cytokine (IL6, TNFá) modulation of beta dysfunction. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.