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Currently seeking M.S. & Ph.D. students.
Associate Professor
Department of Cell Systems & Anatomy
Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are generated during metabolism by mitochondria and by enzymes such as lipoxygenases and NADPH oxidases. Although ROS at low levels may be beneficial by acting as secondary signaling molecules to regulate cellular functions, excessive amounts of ROS induce oxidative damages to cause cell injury and cell death. Neurons’ ravenous demand of energy necessitates high metabolic rates which result in high ROS production. Neurons also have a high load of lipids enriched with polyunsaturated fatty acids that are particularly vulnerable to attack by ROS. Pathological conditions such as accumulation of miss-folded proteins and inflammation can further exacerbate ROS generation in neurons. Indeed, increased ROS are well-demonstrated in neurodegenerative diseases such as Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS), and oxidative damage is believed to be a key pathogenic factor for both. Despite this, antioxidants have so far been disappointing in clinical trials for treatments of neurodegenerative diseases. The main research interest of Ran lab is to illustrate the key events/pathways triggered by ROS that are ultimately responsible for injury and demise of neurons. The goal of our investigation is to identify targets that can be exploited for developing efficacious treatments/interventions. For example, we recently showed that glutathione peroxidase (Gpx4), a master regulator of ferroptosis, is essential for the survival of neurons underlying ALS and AD, suggesting that those neurons are vulnerable to ferroptosis. We are currently trying to determine whether ferroptosis is a key mode of neuron degeneration in ALS and AD and whether ferroptosis and other cell death and survival pathways can serve as targets for therapeutic development for AD and ALS.
Title: Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease.
Project #: 1R01AG064078
Funding Agency: NIA, NIH
Period: 08/2019 - 03/2024
Grant Description: Lipid peroxidation is elevated in Alzheimer’s disease (AD) brains. The goal of this study is to establish the importance of membrane lipid peroxidation in neurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Glutathione peroxidase 4 (Gpx4), a glutathione peroxidase that can suppress lipid peroxidation by directly reducing phospholipid hydroperoxides in membranes, as a target of intervention to retard progression of AD
Title: Gpx4 and ferroptosis inhibition in retarding ALS
Project #: I01 BX003507
Funding Agency: Department of Veterans Affair
Period: 04/2018 - 03/2022
Role: Principal Investigator
Grant Description: The goal of this award is to determine whether inhibition of ferroptosis by Gpx4 overexpression and supplementation of a small molecule inhibitor of ferroptosis can ameliorate paralysis and delay death of ALS mice.
Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, Cao L, Xie M, Ran Q, Kroemer G, Wang H, Billiar TR, Jiang J, Tang D. Lipid Peroxidation Drives Gasdermin D- Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe 2018 Jun;24(1):97-108..
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD..Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017 Oct;171(2):273-285.
Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017 Aug;12:8-17.
Chen L, Hambright WS, Na R, Ran Q. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis. J Biol Chem. 2015 Nov;290(47):28097-280106.
Chen L, Na R, Ran Q. Enhanced defense against mitochondrial hydrogen peroxide attenuates age-associated cognition decline. Neurobiol Aging. 2014 May;35(11):2552-2561.
Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H, Richardson A, Ran Q. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol Med 2012 May;52(9):1820-1827.
Chen L, Yoo SE, Na R, Liu Y, Ran Q. Cognitive impairment and increased Aß levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H(2)O(2). Neurobiol Aging 2012 Feb;33(2):432-432.