Project 2: Effects of metal exposure on EV miRNAs

2024 Jan 22

MEMCARE-SRC Research Update: Project 2

4:00pm

Location: 

HSPH-1 Room 1302 and via Zoom

Quan LuResearch Update: Project 2, Quan Lu and trainees

All MEMCARE-SRC Investigators, trainees and staff are welcome.

Zunwei Chen, Zhi Qiao, Charlotte R Wirth, Hae-Ryung Park, and Quan Lu. 12/2023. “Arrestin domain-containing protein 1-mediated microvesicles (ARMMs) protect against cadmium-induced neurotoxicity.” Extracellular Vesicle, 2, Pp. 100027. Publisher's VersionAbstract
Exposure to environmental heavy metals such as cadmium (Cd) is often linked to neurotoxicity but the underlying mechanisms remain poorly understood. Here we show that Arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs)–an important class of extracellular vesicles (EVs) whose biogenesis occurs at the plasma membrane–protect against Cd-induced neurotoxicity. Cd increased the production of EVs, including ARMMs, in a human neural progenitor cell line, ReNcell CX (ReN) cells. ReN cells that lack ARMMs production as a result of CRISPR-mediated ARRDC1 knockout were more susceptible to Cd toxicity as evidenced by increased LDH production as well as elevated level of oxidative stress markers. Importantly, adding ARMMs back to the ARRDC1-knockout ReN cells significantly reduced Cd-induced toxicity. Consistent with this finding, proteomics data showed that anti-oxidative stress proteins are enriched in ARMMs secreted from ReN cells. Together our study reveals a novel protective role of ARMMs in Cd neurotoxicity and suggests that ARMMs may be used therapeutically to reduce neurotoxicity caused by exposure to Cd and potentially other metal toxicants.
Ross Osgood

Ross Osgood

Project 2 Trainee
Postdoctoral Research Fellow in Environmental Health, Harvard.T.H. Chan School of Public Health
Sengjin Choi, Zhiping Yang, Qiyu Wang, Zhi Qiao, Maoyun Sun, Joshua Wiggins, Shi-Hua Xiang, and Quan Lu. 2023. “Displaying and delivering viral membrane antigens via WW domain-activated extracellular vesicles.” Sci Adv, 9, 4, Pp. eade2708.Abstract

Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle-based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain-activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral membrane proteins displayed on WAEVs elicits production of virus-specific neutralizing antibodies and, in the case of influenza antigens, protects mice from the lethal viral infection. WAEVs thus represent a versatile platform for presenting and delivering membrane antigens as vaccines against influenza, HIV, and potentially many other viral pathogens.

Harvard T.H. Chan School of Public Health

Our Center is based that the Harvard T.H. Chan School of Public Health where the labs of Marc Weisskopf and David Christiani (Project 1), Quan Lu (Project 2), and Tamarra James-Todd (Community Engagement Core) are located in the Department of Environmental Health. The Research Experience and Training Cordination Core (Susan Korrick) and the Administrative (Quan Lu) and Research Translation Core (Trina von Stackelberg) are also based in the Department of Environmental Health. Brent Coull and Xihong Lin's groups (Data Management and Analysis Core) are in the Department of Biostatistics.

Boston Children's Hospital

Takao Hensch's lab in the Boston Children's Hospital Department of Neurology Research studies the neurobiology of critical periods of brain development using mouse models. Dr. Hensch is an Investigator on Project 2.

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