Zhu, K, Mukherjee, K, Wei, C, Hayek, SS, Collins, A, Gu, C, Corapi, K, Altintas, MM, Wang, Y, Waikar, SS, Bianco, AC, Koch, A, Tacke, F, Reiser, J, Sever, S
About Sever Lab
What is our goal?
We aim to convert our fundamental molecular mechanism insights into innovative therapeutics that can positively impact human health. We primarily focus on the role of the GTPase dynamin in regulating cytoskeleton dynamics and clathrin-mediated endocytosis. Dysregulation of these processes has been associated with various human diseases, such as kidney diseases and neurodegenerative disorders.
We are also examining the interplay between the immune system and kidney diseases through our collaboration with clinicians. Gaining a better understanding of diverse molecular mechanisms through which the dynamin and immune system influence cell physiology in a cell-type-specific manner will pave the way for treating human illnesses.
What is our approach?
We use a combination of classic cell biology, biochemistry, single-molecule imaging, animal models, and AI to establish novel paradigms related to the regulation of the cytoskeleton and endocytosis in diverse organ-specific cells. We also use human samples to identify clinically relevant biomarkers and bioassays that define the role of immune-mediated organ injury. Finally, we are actively pursuing the development of novel therapeutics.
Why join the Sever laboratory?
The Sever lab is a welcoming and highly interactive environment. Post-doctoral fellows and research technicians share expertise, reagents, and ideas to reach their common goal of understanding how cytoskeletal dynamics and endocytosis are regulated in healthy and diseased tissue.
We are not only discovering novel molecular mechanisms but are also actively pursuing the development of novel therapies (antibodies, peptides, small molecules) for kidney diseases and neurodegenerative diseases.
Our Research
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Dynamin, a founding member of a superfamily of large GTPases existing in various oligomerization states, is primarily recognized for its involvement in clathrin-mediated endocytosis. Its ability to self-assemble into helices on lipid templates has led to the understanding that dynamin directly initiates the fission reaction, releasing coated pits from the plasma membrane.
Additionally, we've uncovered another distinct role for dynamin oligomerization in regulating the actin cytoskeleton via direct dynamin-actin interactions. The specific molecular mechanisms through which dynamin influences diverse actin-based structures and dynamics vary among cell types.
Our research demonstrates that small molecule allosteric activators of dynamin oligomerization can ameliorate different types of kidney injury. We aim to establish new paradigms regarding molecular mechanisms by which dynamin influences cytoskeleton and endocytosis in a cell-type-specific manner by using a combination of cell biology, biochemistry, biophysics, pharmacology, and AI.
Structure of the dynamin tetramers by AlphaFoldSelected publications
Gu et al. (2010) Dymin directly regulates actin cytoskeleton. EMBO J. 29, 3593-3606.Schiffer et al. (2015). Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nature Medicine 21, 601-609.
Mukherjee et al. (2022). Simultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury. Nature Comm 13, 2422.
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uPAR stands for Urokinase Plasminogen Activator Receptor. It's a cell surface receptor involved in various physiological and pathological processes, particularly in the regulation of cell migration, adhesion, and tissue remodeling. uPAR is closely associated with the plasminogen activation system, which plays a key role in fibrinolysis (the breakdown of blood clots) and extracellular matrix degradation.
uPAR is composed of three homologous domains (D1, D2, and D3), each containing around 90 amino acids. The D2D3 fragment comprises domain 2 and domain 3 of the uPAR protein. These domains are involved in ligand binding and interactions with other proteins.
Originally, the uPAR fragment D2D3 has been studied in various contexts, including cancer biology and inflammation, with a focus on its role in tumor progression, metastasis, and angiogenesis. Recently, we have implicated D2D3 protein in dual organ injury.
Specifically, we have shown that D2D3 injures glomerular podocytes, thus causing chronic kidney diseases. In addition, D2D3 also injures beta-cells of the pancreas, thus causing insulin-dependent diabetes. We are actively pursuing diverse strategies aimed at disrupting the interactions between D2D3 and its ligands or inhibiting the downstream signaling pathways mediated by D2D3, in order to treat kidney diseases and diabetes.
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Structure of avb6 integrin with suPAR (blue ribbons) by AlphaFoldSelected publications
Hayek et al. (2015). Soluble urokinase receptor and chronic kidney disease. NEJM 373, 1916-1925.Hayek et al. (2017). A tripartite complex of suPAR, APOL1 risk variants and avb3 integrin on podocytes mediates chronic kidney diseases. Nature Medicine 23, 945-953.
Zhu et al., (2023). The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease. SciTransl Med. 15, eabq6492.
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Given our insights regarding the role of the actin cytoskeleton and dynamin in the kidney, we hypothesize that actin-based foot processes of podocytes are structurally similar to actin-based dendritic spines in neurons. We hope to demonstrate that targeting the actin cytoskeleton of dendritic spines via dynamin as a proxy may preserve and even reverse early signs of neurodegeneration.
The Sever laboratory is striving to establish a unique environment with SIDD and UTMB, whereby focusing on the basic cellular processes such as dynamin, actin, microtubules, and endocytosis, we can elucidate common and cell-type specific molecular mechanisms that govern highly diverse diseases.
PC12 cells in culture stained with anti-dynamin antibodies (green).
