Dissecting autophagy-based Salmonella clearance in mammalian cells with small-molecule probes
Szu-Yu Meredith Kuo 郭思妤 PhD Candidate, Harvard MCB
PET/MR imaging of neuroreceptor dynamics
Dr. Hsiao-Ying Monica Wey 魏曉英博士 Instructor, Harvard Medical School
Szu-Yu Meredith Kuo 郭思妤 is a brilliant PhD candidate at Harvard, Molecular & Cellular Biology program. She is currently working at Broad institute and she will share with us her work on “Dissecting autophagy-based Salmonella clearance in mammalian cells with small-molecule probes.”
Abstract Macroautophagy (hereafter referred as autophagy) is an evolutionarily conserved catabolic process in eukaryotes, which involves the formation of double-membrane vesicles that enclose cellular components and fuse with lysosomes. In most cell types, autophagy occurs at basal level to maintain cellular homeostasis by degrading cytosolic materials and redistributing nutrients to essential metabolic pathways. Autophagy can also be activated through distinct signaling cascades in response to various stress conditions, including starvation, accumulation of damaged organelles or aggregate proteins, and pathogen invasion. In particular, clearance of invasive bacteria by autophagy has been identified as an important innate immune mechanism with implications for both infectious disease and inflammatory bowel disease. Salmonella enterica serotype Typhimurium (hereafter Salmonella) is an invasive pathogen targeted by autophagy and often used as a model for study this mechanism. In order to acquire a deeper understanding of this mechanism, we conducted a small molecule screen that aimed to identify novel small molecule autophagy modulators, in particular those that promote anti-Salmonella autophagy. We screened 60,000 small molecules prepared by stereoselective, diversity oriented, chemical synthesis. We identified 998 hits emerging from the screen and further prioritized 5 of them based on their chemical structures and activities in secondary assays. Future efforts are undergoing to further explore the mechanisms of action of these small molecules probes and explore their potentials in therapeutics.
Dr. Hsiao-Ying Monica Wey 魏曉英博士 is currently an instructor in Radiology at Harvard Medical School and Assistant in Biomedical engineering at Mass General Hospital. Her research focuses on technical developments of simultaneous PET/MRI for neuroscience application. In this seminar she will talk about her work on “PET/MR imaging of neuroreceptor dynamics”. http://www.nmr.mgh.harvard.edu/~wey/
Abstract Whole-brain human neuroimaging studies to date have made an impact by advancing high-resolution anatomy and investigating brain function through structural and functional connections. Yet, our understanding of neurochemical connections, their dynamic interactions and its effect on high-level brain function is limited, even though these aspects are of utmost importance for any drug acting on neurochemical pathways in the brain.This talk will give an overview of recent advances in functional and molecular imaging using simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) with an integrated PET/MR scanner. This unique combination of modalities allows us to explore neuroreceptor dynamics, neurochemical connections and their effects on brain function. We will present novel imaging methods and how they can assess relationships between receptor occupancy and changes in brain activity due to pharmacological challenges targeting the dopamine and opioid systems. We will show that these techniques allow to image receptor adaptation mechanisms in vivo, such as receptor internalization. Moreover, interactions between receptor systems and their functional connections can be measured dynamically. Imaging such dynamics and connections plays an important role for understanding drug action and function of neurochemical pathways in the brain and is crucial for creating and evaluating drug treatment of neurological and psychiatric disorders.