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SUMMARY:RNA Innovation Seminar: John Lueck\, Ph.D.\, Associate Professor\, Pharmacology and Physiology; Neurology\, University of Rochester Medical Center
DESCRIPTION:“Development of ACE-tRNAs as a platform therapeutic for nonsense-associated diseases”\nJohn D. Lueck\, Ph.D.\nAssociate Professor\nPharmacology and Physiology\nNeurology\nUniversity of Rochester Medical Center\n  \nIn-person: ABC Seminar Rooms\, BSRB | Hybrid link \nCo-hosted by the Cystic Fibrosis at UM Initiative \n\nAbstract:\nWe have generated a library of AntiCodon Edited (ACE) -tRNAs that are capable of suppressing disease-causing nonsense mutations and rescuing WT protein function. However\, to advance ACE-tRNAs as a therapeutic\, we set out to determine how well they function as a platform therapeutic\, where one ACE-tRNA sequence encoding one amino acid can be used to restore significant function of the target protein with nonsense to missense mutations. This maneuver would significantly reduce the burden of advancing several ACE-tRNA sequences through clinical trials and FDA approval. Further\, we are working to determine modalities for viral and non-viral delivery of ACE-tRNAs to different tissues. In doing so\, we have taken advantage of the diminutive size of the ACE-tRNA expression cassette to generate small DNA vectors for efficient cell delivery and nuclear targeting. \nBiography:\nThe 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. \nResearch interests:\nMy 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. \nLinks:\nJohn D. Lueck\, Ph.D. | University of Rochester Medical Center Faculty Page\nLueck Lab\nJohn D. Lueck | Google Scholar
URL:https://rna.umich.edu/events/rna-innovation-seminar-john-lueck-ph-d-associate-professor-pharmacology-and-physiology-neurology-university-of-rochester-medical-center/
LOCATION:BSRB – ABC Seminar rooms\, 109 Zina Pitcher Pl\, Ann Arbor\, MI\, 48109\, United States
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