Scott Hansen, PhD

Associate Professor
Department of Molecular Medicine
Florida Campus


 Email

Scripps Research Joint Appointments

Department of Neuroscience
Faculty, Graduate Program

Research Focus

Our laboratory studies the role of cholesterol in setting thresholds of anesthesia, mechanosensation, amyloid formation, and viral entry. In each area of research, we study how cholesterol controls the threshold that regulates biological function and the severity of disease. By understanding the thresholds, we aim to treat diseases caused by altered cholesterol levels and signaling lipids.

Anesthesia: For hundred years scientist believed that membrane lipids were involved in the anesthesia (reversible loss of consciousness). At the heart of the question was the following, How can disrupting a lipid membrane activate or inhibit and ion channel? We have shown that anesthetics disrupt compartmentalization of signaling molecules in cholesterol dependent lipid compartments. The anesthetics counteract cholesterol causing the proteins to escape and activate an ion channel. This established at least one clear molecular mechanism for the membrane as a target of inhaled anesthetics. We are studying this mechanism for additional ion channels that mediate anesthesia in people.

Pain threshold (mechanosensation): We have shown mechanical force disrupts cholesterol dependent compartmentalization of proteins, similar to anesthetics. In addition to defining a novel mechanosensation pathway, we are developing potential therapeutic compounds that will activate an analgesic channel downstream of mu opioid receptor. We aim to develop therapeutics that will have similar pain reducing benefits as opioids, but without the addiction.

Viral entry: We have recently proposed a model for cholesterol dependent SARS-COV-2 viral infectivity, based on our understanding of cholesterol mediated membrane protein translocation. As cholesterol increases the ability of the virus to enter the cell increases. Increased viral entry increases inflammation, which in turn increases cholesterol and more viral entry. We are currently studying cholesterol loading in lung tissues in aged animals.

The lab is currently seeking highly motivated individuals who are interested in multicsciplenary research in these areas. To apply please inquire at shansen@scripps.edu.


Education

Ph.D., University of California, San Diego, 2006
B.S. (Chemistry), Utah State University, 1999

Professional Experience

2017-2018 Assistant Professor, Molecular Medicine, Scripps Research
2012-2018 Assistant Professor (Joint Appointment), Neuroscience, Scripps Research
2012-2017 Assistant Professor, Molecular Therapeutics, Scripps Research
2000-2000 Research Associate, Scripps Research
1999-2000 Laboratory Technician, Abbott Laboratories

Awards & Professional Activities

Eicosanoid Research Foundation 2017 Young Investigator Award
NIH Director's New Innovator Award, DP2 (2013)
Postdoctoral Fellowship (2007-2011) Howard Hughes Medical Institute
Martin D. Kamen Award (2006), best doctoral thesis; University of California, San Diego
Young Scientist Travel Award (2006) American Society of Pharmacology and Experimental Therapeutics
Dissertation Fellowship (2003-2005) Tobacco Related Disease Research Program

Selected References

All Publications

Hauseman ZJ, Harvey EP, Newman CE, Wales TE...Hansen SB, Wu H, Gygi SP, Engen JR, Walensky LD., "Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization" Molecular Cell, June 12, 2020. https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30349-X

Mahmud Arif Pavel, E. Nicholas Petersen, Hao Wang, Richard A. Lerner, and Scott B. Hansen. "Studies on the mechanism of general anesthesia." (2020) Proceedings of the National Academy of Sciences  28 May. https://www.pnas.org/content/early/2020/05/27/2004259117

Hao Wang, Zixuan Yuan, Mahmud Arif Pavel, Scott B. Hansen. The role of high cholesterol in age-related COVID19 lethality. May 2020 https://www.biorxiv.org/content/10.1101/2020.05.09.086249v3.article-metrics#details

Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels. E. Nicholas Petersen, Mahmud Arif Pavel, Hao Wang, Scott B.Hansen. (2020) BBA Biomembranes 1862 (1) pg1-9. https://www.sciencedirect.com/science/article/pii/S0005273619302378?via%3Dihub

E. Nicholas Petersen, Manasa Gudheti, Mahmud Arif Pavel, Keith R. Murphy, William W. Ja, Erik M. Jorgensen, Scott B. Hansen. Phospholipase D Transduces Force to TREK-1 Channels in a Biological Membrane. (2019) BioRxiv. https://www.biorxiv.org/content/10.1101/758896v1

Pavel MA, Chung HW, Petersen EN., Hansen SB. "Polymodal Mechanism for TREK-1 Inhibition by Local Anesthetic " (2019) Anesth. & Analg. 2019 Oct;129(4):973-982. https://journals.lww.com/anesthesia-analgesia/Abstract/2019/10000/Polymodal_Mechanism_for_TWIK_Related_K__Channel.12.aspx

Robinson CV, Rohacs T, and Hansen SBTools for understanding nanoscale lipid regulation of ion channels. 2019 Trends Biochem Sci. 2019 Sep;44(9):795-806. https://www.sciencedirect.com/science/article/abs/pii/S0968000419300817

Hae-Won Chung JMB 2018 Chung HW, Petersen EN, Cabanos C, Murphy KR, Pavel AP, Hansen AS, Ja WW, Hansen SB (2018) A Molecular Target for an Alcohol Chain-length Cutoff (2019) J Mol Biol. Jan 18;431(2):196-209. https://doi.org/10.1016/j.jmb.2018.11.028

Nayebosadri, Arman and Petersen, E. Nicolas and Cabanos, Cerrone and Hansen, Scott B., A Membrane Thickness Sensor in TREK-1 Channels Transduces Mechanical Force (2018). Available at SSRN: https://ssrn.com/abstract=3155650 or http://dx.doi.org/10.2139/ssrn.3155650

Cabanos C, Wang M, Han X, Hansen SB (2017) A Soluble Fluorescent Binding Assay Reveals PIP2 Antagonism of TREK-1 Channels. Cell Rep 20(6):1287–1294. https://www.cell.com/cell-reports/pdfExtended/S2211-1247(17)31000-8

E. Nicholas Peteresen, Hae-Wng Chung, Arman Nayebosadri, and Scott B. Hansen "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D" Nature Commun. 2016 Dec (7) 13873; https://www.nature.com/articles/ncomms13873

Hansen SB “Lipid Agonism; the PIP2 Paradigm of ligand gated ion channels” Biochim Biophys Acta 2015 May 1851 (5): 620-628. https://www.sciencedirect.com/science/article/pii/S1388198115000232?via%3Dihub

Hansen SB, Xiao Tao, Roderick MacKinnon “Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2” Nature 2011, 477:495-98

Gao F, Mer G, Tonelli M, Hansen SB, Burghart TP, Taylor P, Sine SM. “Solution NMR of Acetycholine Binding Protein Reveals ACh-mediated Conformational Change of the C-loop” Mol Pharmacol. 2006 Oct 70(4): 1230-5

Hansen SB, Wang, HL, Taylor P, and Sine SM “An Ion-Selectivity Filter in the Extracellular Domain of Cys-loop Receptors Reveals Determinants for Ion Conductance. J Biol Chem. 2008 Dec 26:283(52):36066-70

Hansen SB and Taylor P “Galanthamine and Non-competitive Inhibitor Binding to ACh-binding Protein: Evidence for a Binding Site on Non-a-subunit Interfaces of Heteromeric Neuronal Nicotinic Receptors” J. Mol. Biol. 2007 June 369, 895-901 

Bourne Y, Talley TT, Hansen SB, Taylor P and Marchot P “Crystal structure of a Cbtx-AChBP complex reveals essential interaction between snake a-neurotoxins and nicotinic receptors” Embo J 2005, 24: 1512-22

Hibbs RE, Johnson DA, Shi J, Hansen SB, and Taylor P “Structural Dynamics of the a-Neurotoxin-Acetylcholine Binding Protein Complex: Hydrodynamic and Fluorescence Anisotropy Decay Analyses” Biochemistry 2005, 44:16602-11

Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, and Bourne Y “Structures of Aplysia AChBP complexes with agonists and antagonists reveal distinctive binding interfaces and conformations” Embo J 2005, 24:3635-46

Gao F, Bren N, Burghardt TP, Hansen SB, Henchman RH, Taylor P, McCammon JA, Sine SM. “Agonist-mediated conformational changes in acetylcholine-binding protein revealed by simulation and intrinsic tryptophan fluorescence” J Biol Chem. 2005 Mar 4;280(9):8443-51

Bouzat C, Gumilar F, Spitzmaul G, Wang HL, Rayes D, Hansen SB, Taylor P, and Sine SM “Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel” Nature 2004 Aug 19:430:896-900

Hansen SB, Talley TT, Radic Z, and Taylor P. “Structural and ligand recognition characteristics of an acetylcholine binding protein from Aplysia californica” J Biol Chem. 2004 Jun 4:279(23):24197-202

Gao F, Bern N, Little A, Wang HL, Hansen SB, Talley TT, Taylor P, and Sine SM. “Curariform antagonists bind in different orientations to acetylcholine-binding protein” J Biol Chem. 2003 Jun 20;278(25):23020-6.

Hansen SB, Radic Z, Talley TT, Molles BE, Deerinck T, Tsigelny I, and Taylor P. “Tryptophan fluorescence reveals conformational changes in the acetylcholine binding protein” J Biol Chem. 2002 Nov 1;277(44):41299-302.

Issued Patents

Hansen SB, Radic Z, and Taylor P “Methods for identifying agents that modulate LGIC receptor activity.” United States Patent 7947466. 24 May 2011

Hansen SB, Hansen AS "Methods for identifying molecules that modulate lipid binding sites of ion channels" United States Patent 8669065. 11 March 2014 


Links

New Innovator Award 2013

Pubmed Citations

Neuroscience page

Press release, Appointment

Faculty of 1000

Webvision: notable paper

Google Scholar