Paul

Valdmanis

PhD

biography

Dr. Valdmanis is originally from Toronto, Canada and received his bachelor’s in science in biochemistry summa cum laude from the University of Ottawa.  He then completed his PhD in the laboratory of Guy Rouleau in the Department of Human Genetics at McGill University in Montreal, Canada. His research focused on the identification of pathogenic variants in genes responsible for Amyotrophic Lateral Sclerosis, Hereditary Spastic Paraplegia, and Sensory Ataxia, while supported by fellowships from the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canadian Institutes of Health Research (CIHR) and the Fonds de Recherche en Sante Quebec (FRSQ).

He conducted his postdoctoral research at Stanford University in the lab of Mark Kay in the Departments of Pediatrics and Genetics where he was a Banting Postdoctoral Fellow and a Bisby Postdoctoral Fellow. There he established methods to identify how to safely and effectively reduce target genes by utilizing adeno-associated viral delivery of short hairpin RNAs. Dr. Valdmanis joined the Division of Medical Genetics at the University of Washington in 2017 as an Assistant Professor.

Education & Training 

Bachelor's Degree in Science, University of Ottawa (2003)

PhD, McGill University (2009)

Honors

Roger Guindon Scholarship (2000)

CIHR Institute of Neurosciences Brain Star Award (2008)

Governor General’s Gold Medal, McGill University (2009)

Gordon A. Maclachlan Prize, McGill University (2009)

American Society of Gene and Cell Therapy Research Excellence Award (2011)

American Society of Gene and Cell Therapy Travel Award (2011, 2012, 2014, 2016)

Robert F. Schoeni Award for Research, Ann Arbor Active Against ALS, (2019)

Research Interests

 

The Valdmanis lab studies genetic risk factors for neurodegenerative diseases such as Alzheimer's disease and Amyotrophic Lateral Sclerosis and gene therapy methods for therapeutic intervention. Through a series of studies focusing on long-read sequencing of the genome and transcriptome, his group has identified tandem repeats that expand in individuals and complex alternative splicing patterns that accumulate as a function of age and neurodegenerative disease, especially at the synapse.

The Valdmanis lab focuses on the following research goals:

1.  Identify novel genetic contributors to Amyotrophic Lateral Sclerosis and Alzheimer's disease, including tandem repeat expansions using long-read sequencing technology.

2. Develop gene therapy methods for safe and effective gene knockdown using recombinant adeno-associated viral vectors (AAVs) to target genes implicated in neurodegeneration.

3. Perform mechanistic characterization of the role of microRNAs including miR-122 and an imprinted cluster of microRNAs at the DLK1-DIO3 locus in the development of hepatocellular carcinoma. 

Publications

 

Valdmanis PN, Kay MA. Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond. Human Gene Therapy. 2017 Apr;28(4):361-372.

Valdmanis PN, Gu S, Chu K, Jin L, Zhang F, Munding EM, Huang Y, Kutay H, Ghoshal K, Lisowski L, Kay MA. RNA interference-induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice. Nature Medicine 2016 May;22(5)557-62.

Valdmanis PN, Roy-Chaudhuri B, Kim HK, Sayles LC, Zheng Y, Chuang CH, Caswell DR, Chu K, Zhang Y, Winslow MM, Sweet-Cordero EA, Kay MA. Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma. Oncogene. 2015 Jan 2;34(1):94-103.

Barzel A, Paulk NK, Shi Y, Huang Y, Chu K, Zhang F, Valdmanis PN, Spector, LP, Porteus MH, Gaensler KM, Kay MA. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature 2015 Jan 15;517(7534):360-4.

Roy-Chaudhuri B, Valdmanis PN, Zhang Y, Wang Q, Luo QJ, Kay MA. Regulation of microRNA-mediated gene silencing by microRNA precursors. Nature Structural & Molecular Biology 2014 Sep;21(9):825-32. 

Gu S, Jin L, Zhang Y, Huang Y, Zhang F, Valdmanis PN, Kay MA. The loop position of shRNAs and pre-miRNAs is critical for the accuracy of dicer processing in vivo. Cell 2012 Nov 9;151(4):900-11.

Valdmanis PN, Gu S, Schüermann N, Sethupathy P, Grimm D, Kay MA. Expression determinants of mammalian argonaute proteins in mediating gene silencing. Nucleic Acids Research 2012 Apr;40(8):3704-13.

Valdmanis PN, Dupré N, Lachance M, Stochmanski S, Belzil VV, P.A. Dion PA, I. Thiffault, B. Brais, L. Weston, L. Saint-Amant, M.E. Samuels and Rouleau GA. A mutation in the RNF170 gene causes autosomal dominant sensory ataxia. Brain 2011 Feb;134(Pt 2):602-7.

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. Mutations in the FUS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009 Feb 27;323(5918):1205-8.

Kabashi E*, Valdmanis PN*, Dion PA, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard J-P, Lacomblez L, Pochigayeva K, Salachas F, Pradat P-F, Camu W, Meininger V, Dupré N and Rouleau GA. TARDBP mutations in sporadic and familial ALS patients. Nature Genetics 2008 May; 40(5):572-4.

Valdmanis PN*, Meijer IA*, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, and Rouleau GA. Mutations in the KIAA0196 gene at the SPG8 locus cause Hereditary Spastic Paraplegia. American Journal of Human Genetics 2007 Jan; 80(1): 152-61.