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John D. Lueck, Ph.D.

John D. Lueck, Ph.D.

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Center for RNA Biology

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About Me

The focus of my research is to evaluate the therapeutic promise of suppressor tRNA for treatment of cystic fibrosis. In my graduate training I studied myotonia in myotonic dystrophy type 1 (DM1) in Dr. Robert Dirksen’s laboratory and in collaboration with Dr. Charles Thornton. I used both molecular...
The focus of my research is to evaluate the therapeutic promise of suppressor tRNA for treatment of cystic fibrosis. In my graduate training I studied myotonia in myotonic dystrophy type 1 (DM1) in Dr. Robert Dirksen’s laboratory and in collaboration with Dr. Charles Thornton. I used both molecular biology/genetics and electrophysiology approaches to determine how the DM1-associated problems with alternative splicing affect function of ClC-1 chloride channel and muscle excitability. I showed that chloride conductance is rapidly rescued if ClC-1 splicing is corrected or if sequestration of splicing factors is released. I also investigated the effects of splicing misregulation on function of RyR1. These studies resulted in 10 publications and cemented my interest in doing translational research. Following my graduate work, I joined Dr. Kevin Campbell’s laboratory. There I learned membrane protein biochemistry, antibody generation and testing mouse skeletal muscle physiology testing and gene therapy approaches, in studies focused on muscular dystrophy. This experience makes me well suited to conduct independent research using a breadth of techniques focused disease pathogenesis. My research took a turn as I became interested in the field of genetic code expansion and its use as a therapeutic for cystic fibrosis (CF) that result from nonsense mutations. I quickly published 5 studies in 3 years with Dr. Chris Ahern that propelled me to my current independent position, where I have been able to extend my research in determining the therapeutic promise of our suppressor tRNA technologies for CF. In my next steps, I will use my extensive training in mouse genetics, molecular biology, membrane biophysics and protein biochemistry to investigate the impact on cellular and tissue processes following stop codon suppression in vivo and generate new CF therapeutic deliverables that can be translated into other nonsense associated diseases. More broadly, I'm interested in applying membrane biophysics and molecular and cellular biology approaches to elucidate the molecular underpinning of genetic diseases, and then using mechanistic insights to develop new treatments.

Faculty Appointments

Associate Professor - Department of Pharmacology and Physiology (SMD)

Associate Professor - Department of Neurology, NMD (SMD) - Joint

Research

My research focuses on the molecular genetics and experimental treatment of diseases resulting from nonsense mutations. I am investigating the use of engineered tRNAs for suppression of nonsense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) transcripts as therapeutic inter...
My research focuses on the molecular genetics and experimental treatment of diseases resulting from nonsense mutations. I am investigating the use of engineered tRNAs for suppression of nonsense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) transcripts as therapeutic intervention for cystic fibrosis. Additionally, I am interested in the molecular genetics and experimental treatment of the trinucleotide repeat disorder myotonic dystrophy (DM1). Moving forward, I intend to study pre-mRNA splicing defects in DM1 to determine the causes of muscle weakness and wasting, and develop and test new therapeutic strategies to target the genetic misstep and reverse symptoms. More broadly, I'm interested in applying membrane biophysics, molecular and cellular biology approaches to understand the molecular underpinning of genetic diseases and develop therapeutic interventions.

Publications

Journal Articles

Optimization of ACE-tRNAs function in translation for suppression of nonsense mutations.

Porter JJ, Ko W, Sorensen EG, Lueck JD

Nucleic acids research.. 2024 November 30 Epub 11/30/2024.

Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.

Bhat S, Bhattacharya A, Li H, Lueck JD, Goldman YE, Cooperman BS

bioRxiv : the preprint server for biology.. 2024 November 14 Epub 11/14/2024.

Gz Enhanced Signal Transduction assaY (GESTY) for GPCR deorphanization.

Franchini L, Porter JJ, Lueck JD, Orlandi C

bioRxiv : the preprint server for biology.. 2024 July 26 Epub 07/26/2024.

A cystic fibrosis gene editing approach that is on target.

Porter JJ, Lueck JD

Molecular therapy. Nucleic acids.. 2024 June 1135 (2):102197. Epub 05/08/2024.

Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model.

Cisco LA, Sipple MT, Edwards KM, Thornton CA, Lueck JD

The Journal of clinical investigation.. 2024 January 2134 (1)Epub 01/02/2024.

Photomodulation of the ASIC1a acidic pocket destabilizes the open state.

Rook ML, McCullock TW, Couch T, Lueck JD, MacLean DM

Protein science : a publication of the Protein Society.. 2023 November 32 (11):e4800. Epub 1900 01 01.

Combinatorial chloride and calcium channelopathy in myotonic dystrophy.

Cisco LA, Sipple MT, Edwards KM, Thornton CA, Lueck JD

bioRxiv : the preprint server for biology.. 2023 June 1 Epub 06/01/2023.

Gene, RNA, and ASO-based therapeutic approaches in Cystic Fibrosis.

Allaire NE, Griesenbach U, Kerem B, Lueck JD, Stanleigh N, Oren YS

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.. 2023 March 22 Suppl 1 (Suppl 1):S39-S44. Epub 01/17/2023.

Efficient suppression of endogenous CFTR nonsense mutations using anticodon-engineered transfer RNAs.

Ko W, Porter JJ, Sipple MT, Edwards KM, Lueck JD

Molecular therapy. Nucleic acids.. 2022 June 1428 :685-701. Epub 05/04/2022.

Therapeutic promise of engineered nonsense suppressor tRNAs.

Porter JJ, Heil CS, Lueck JD

Wiley interdisciplinary reviews. RNA.. 2021 July 12 (4):e1641. Epub 02/10/2021.

?11-12 linker isomerization governs acid-sensing ion channel desensitization and recovery.

Rook ML, Williamson A, Lueck JD, Musgaard M, Maclean DM

eLife.. 2020 February 79 Epub 02/07/2020.

Engineered transfer RNAs for suppression of premature termination codons.

Lueck JD, Yoon JS, Perales-Puchalt A, Mackey AL, Infield DT, Behlke MA, Pope MR, Weiner DB, Skach WR, McCray PB, Ahern CA

Nature communications.. 2019 February 1810 (1):822. Epub 02/18/2019.

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel.

Molinarolo S, Lee S, Leisle L, Lueck JD, Granata D, Carnevale V, Ahern CA

The Journal of biological chemistry.. 2018 April 6293 (14):4981-4992. Epub 01/25/2018.

Orthogonality of Pyrrolysine tRNA in the Xenopus oocyte.

Infield DT, Lueck JD, Galpin JD, Galles GD, Ahern CA

Scientific reports.. 2018 March 268 (1):5166. Epub 03/26/2018.

Cellular encoding of Cy dyes for single-molecule imaging.

Leisle L, Chadda R, Lueck JD, Infield DT, Galpin JD, Krishnamani V, Robertson JL, Ahern CA

eLife.. 2016 December 125 Epub 12/12/2016.

Atomic mutagenesis in ion channels with engineered stoichiometry.

Lueck JD, Mackey AL, Infield DT, Galpin JD, Li J, Roux B, Ahern CA

eLife.. 2016 October 65 Epub 10/06/2016.

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy.

Beedle AM, Turner AJ, Saito Y, Lueck JD, Foltz SJ, Fortunato MJ, Nienaber PM, Campbell KP

The Journal of clinical investigation.. 2012 September 122 (9):3330-42. Epub 08/27/2012.

Allele-specific gene silencing in two mouse models of autosomal dominant skeletal myopathy.

Loy RE, Lueck JD, Mostajo-Radji MA, Carrell EM, Dirksen RT

PloS one.. 2012 7 (11):e49757. Epub 11/12/2012.

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice.

Han R, Frett EM, Levy JR, Rader EP, Lueck JD, Bansal D, Moore SA, Ng R, Beltrán-Valero de Bernabé D, Faulkner JA, Campbell KP

The Journal of clinical investigation.. 2010 December 120 (12):4366-74. Epub 11/08/2010.

Sarcolemmal-restricted localization of functional ClC-1 channels in mouse skeletal muscle.

Lueck JD, Rossi AE, Thornton CA, Campbell KP, Dirksen RT

The Journal of general physiology.. 2010 December 136 (6):597-613. Epub 11/15/2010.

Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.

Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, Thornton CA

Science.. 2009 July 17325 (5938):336-9. Epub 1900 01 01.

Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling.

Kimura T, Lueck JD, Harvey PJ, Pace SM, Ikemoto N, Casarotto MG, Dirksen RT, Dulhunty AF

Cell calcium.. 2009 March 45 (3):264-74. Epub 01/07/2009.

Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy.

Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA

The Journal of clinical investigation.. 2007 December 117 (12):3952-7. Epub 1900 01 01.

Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1.

Lueck JD, Lungu C, Mankodi A, Osborne RJ, Welle SL, Dirksen RT, Thornton CA

American journal of physiology. Cell physiology.. 2007 April 292 (4):C1291-7. Epub 11/29/2006.

Muscle chloride channel dysfunction in two mouse models of myotonic dystrophy.

Lueck JD, Mankodi A, Swanson MS, Thornton CA, Dirksen RT

The Journal of general physiology.. 2007 January 129 (1):79-94. Epub 12/11/2006.

Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse.

Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology.. 2006 February 20 (2):329-30. Epub 11/11/2005.

Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1.

Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, Dirksen RT, Takahashi MP, Dulhunty AF, Sakoda S

Human molecular genetics.. 2005 August 114 (15):2189-200. Epub 06/22/2005.