R. Luke Wiseman, PhD
Professor
Department of Molecular and Cellular Biology
Professor, Berwyn Maple Endowed Chair
Research Focus
The human body is constantly challenged with a wide array of genetic, environmental, or aging-related insults (or stress). To confront these challenges, the body utilizes a network of stress-responsive signaling pathways that protect cells from various types of insult. These pathways similar mechanisms involving the sensing of a defined stress and subsequent activation of signaling cascades that promote protective remodeling of the cellular proteome. As such, these pathways are continuously responding to environmental changes to mitigate damage associated with the invariability of the cellular environment and ensure effective cellular and tissue function. Considering the importance of stress-signaling pathways in maintaining cellular and organismal function, it is not surprising that genetic or aging-associated changes in the activity of these pathways is implicated in the onset and pathogenesis of many different diseases. Our interests primarily focus on defining the pathologic implications of stress-responsive signaling pathways in human disease with the explicit goal of identifying potential aspects of these pathways that can be therapeutically targeted to improve outcomes across many disorders. In other words, we are looking to identify ways to ‘hijack’ the body’s own defense mechanisms to prevent pathological imbalances in cellular physiology associated with diverse diseases.
Our primary focus is studying stress-responsive signaling pathways involved in regulating cellular protein homeostasis (or proteostasis) such as the unfolded protein response (UPR), integrated stress response (ISR), and heat shock response (HSR). These pathways function to maintain the integrity of the cellular proteome and prevent the potentially toxic accumulation of proteins that can disrupt cellular physiology. Imbalances in proteostasis are implicated in many different types of disease including neurodegenerative diseases, protein misfolding diseases, metabolic disorders, cardiovascular diseases, and inflammatory diseases. As we focus on defining the specific mechanisms by which these stress-responsive pathways protect cells against disease-relevant insults, we are identifying new opportunities to mitigate pathologies associated with many different types of human diseases. Through these efforts, we are working to develop unique strategies that can potentially be applied widely to treat human diseases in a ‘one-drug:multiple disease’ therapeutic paradigm.
Select Publications
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Perea, Valerie; Cole, Christian; Lebeau, Justine; Dolina, Vivian; Baron, Kelsey R; Madhavan, Aparajita; Kelly, Jeffery W.; Grotjahn, Danielle Ann; Wiseman, Rockland Luke PERK Signaling Promotes Mitochondial Elongation by Remodeling Membrane Phosphatidic Acid. EMBO Journal 2023, 42, e113908.
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Rosarda, Jessica D.; Giles, Sarah; Harkins-Perry, Sarah; Mills, Eliz A.; Friedlander, Martin; Wiseman, R L.; Eade, Kevin T. Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity. Nature Communications 2023, 14, 4119.
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Brown, Steven J.; Chen, John J.; Cooley, Christina B.; Dobbs, Wesley; Gallagher, Ciara M.; Garza, Dan; Genereux, Joseph C.; Hodder, Peter; Kelly, Jeffery W.; Madoux, Franck; Paxman, Ryan J.; Plate, Lars; Powers, Evan T.; Rosen, Hugh; Scampavia, Louis; Spicer, Timothy P.; Walter, Peter; Wiseman, R L. Author response: Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. eLife 2016.
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Yang, Jie; Baron, Kelsey R.; Pride, Dani E.; Schneemann, Anette; Guo, Xiaoyan; Chen, Wenqian; Song, Albert S.; Aviles, Giovanni; Kampmann, Martin; Luke Wiseman, R; Lander, Gabriel C. DELE1 oligomerization promotes integrated stress response activation. 2023.
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Madhavan, Aparajita; Kok, Bernard P.; Rius, Bibiana; Grandjean, Julia M.; Alabi, Adekunle; Albert, Verena; Sukiasyan, Ara; Powers, Evan T.; Galmozzi, Andrea; Saez, Enrique; Wiseman, R L. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.. Nature communications 2022, 13, 608.
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Rius, Bibiana; Mesgarzadeh, Jaleh S.; Romine, Isabelle C.; Paxman, Ryan J.; Kelly, Jeffery W.; Wiseman, R L. Pharmacologic targeting of plasma cell endoplasmic reticulum proteostasis to reduce amyloidogenic light chain secretion.. Blood Advances 2021, 1037-1049.
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Grandjean, J. M.; Madhavan, Aparajita; Cech, L.; Seguinot, B. O.; Paxman, Ryan J.; Smith, E.; Scampavia, Louis D.; Powers, Evan T.; Cooley, C. B.; Plate, L.; Spicer, Timothy P.; Kelly, Jeffery W.; Wiseman, Rockland L. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nature Chemical Biology 2020.
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Puchades Garcia, Cristina; Rampello, A. J.; Shin, Mia; Giuliano, C. J.; Wiseman, Rockland L.; Glynn, S. E.; Lander, Gabriel C. Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing. Science 2017, 358.
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