Charles H.

Applications

"A Dr. Charles H. Best Postdoctoral Fellowship will be awarded to a highly qualified graduate (2 years or less postgraduate) in the field of molecular, genetic and genomic research. Applications should be addressed to one or two primary faculty members in the Donnelly Center for Cellular and Biomolecular Research (Andrews, Bader, Blencowe, Boone, Caudy, Emili, Fraser, Greenblatt, Hughes, Kim, Krause, Moffat, Morris, Roth, Ryu, Sidhu, Taipale, Zhang), whose interests match their own. Individual research programs include studies on gene regulation, signal transduction, development, systems biology, proteomics, computational biology and functional genomics and are carried out in the state-of-the-art Donnelly Centre . Upon agreement of sponsorship, the applicant must send a curriculum vitae, one page statement of research interests, transcripts, and three letters of reference to their sponsoring faculty mentor. The deadline for applications is late September annually. The successful applicant will be supported for up to two years with a generous stipend.

Descriptions of Recent Projects


Juline Poirson, PhD, University of Strasbourg-2019


Juline Poirson

Cell homeostasis is regulated by a variety of molecular pathways among which the ubiquitin proteasome system, or UPS, plays a key role. The UPS regulates protein stability by degrading the proteins which are no longer needed. As a form of waste disposal and recycling, the UPS can be found across the tree of life, from the simple yeast cells to the more complex cells that make up the human body. Given its central role to the normal functioning of the cell, the UPS often goes haywire in disease, including cancer. A better understanding of the its role in cancer has the potential to uncover new therapeutic targets.

The UPS comprises a complex network of enzymes which ultimately recognize proteins destined for degradation and label them with ubiquitin, a small protein named after its ubiquitous presence in diverse cells. Proteins labeled by ubiquitin are then delivered to the proteasome, a large cellular machinery in which they are degraded. There are about 600 E3 ligases, enzymes that attach ubiquitin to target proteins, or substrates, in human cells. Each E3 ligase recognizes a set of substrates, but our knowledge about which substrates are recognized by each individual E3 is far from complete. Because E3 ligases confer substrate specificity, mapping the E3 ligase-substrate pairs is central to understanding the UPS’ roles in cells and also in disease.

Juline Poirson, the 2019 Charles H. Best Fellow, has set out to discover and characterise interactions between E3 ligases and proteins involved in tumorigenesis. She has so far identified about 20 protein substrates, out of a pool of 450 known cancer drivers, whose abundance in cells increases upon inhibiting the UPS, suggesting they are targeted for the degradation. This is already an important new insight as the majority of these proteins have not been previously linked to the UPS. Poirson is now working to map each cancer driver protein to its cognate E3 ligase. She will also further characterise these molecular interactions and explore new ones using the CRISPR gene editing technology to functionally eliminate some 1200 UPS-related genes. And because E3-substrate interactions are highly specific, they make good drug targets — inhibiting them by drugs is more likely to have a specific outcome and fewer side effects, in contract to the widely used chemotherapy. Poirson’s research carried out in Mikko Taipale’s laboratory will therefore provide novel insights about how E3 ligases contribute to tumorigenesis and could open new avenues for developing personalized cancer treatments.

Poirson joined Mikko Taipale’s lab two years ago to study how protein stability contributes to cancer.

“I am really thankful for the fellowship,” says Poirson. “It’s a great support for me to encourage me to continue to do what I love the most, which is science.”

Before joining Taipale’s lab, Poirson completed her doctoral studies at the University of Strasbourg in France with Drs. Murielle Masson and Gilles Travé. There she studied how human papilloma virus, which causes cervical cancer, overcomes the host cell’s defense mechanism. The virus does this by co-opting the ubiquitin proteasome system, which remains the focus of her research.

“Juline did her PhD on high-throughput protein/protein interactions in the ubiquitin/proteasome field so she has the perfect background for the project,” says Taipale, who is also Assistant Professor in U of T’s Department of Molecular Genetics. “She’s also a great lab member and we are very lucky to have her expertise at hand. I’m convinced she will make major contributions to our understanding of the ubiquitin-proteasome system in cancer and other diseases.”

Jiabao Liu, PhD Peking Union Medical College - 2018


Nuclear receptors (NRs) are proteins that reside inside many cell types in the body. They recognize and bind to certain simple chemicals (called ligands), hormones for example. Ligands in the blood stream bind to a specific NR, enables it to bind to specific regions of the DNA, affecting the expression of particular genes and resulting in distinct physiological or pathological effects. Thus NRs play key roles in embryo development and cellular equilibrium, as well as in many metabolic disorders such as obesity, diabetes and cancer. Because of this they are ideal targets for drug discovery. Fully 13% of the approved pharmaceuticals target NRs, and a third of known human NRs are targets of currently marketed drugs. Among all 48 human NRs, 24 are so-called ‘orphan’ receptors, meaning the simple chemical that binds to them has not yet been identified. A study of this class of NRs will prove fertile ground, because they suggest the existence of many previously unknown signaling pathways that may be regulated by undiscovered endogenous ligands.

RORs, one class of nuclear receptors, play a regulatory role in lipid/glucose regulation and various immune functions, They have been implicated in a medical disorder known as metabolic syndrome and in several inflammatory diseases. In particular two RORs, RORa and ROR?, are considered to be master regulators of Th17 cells, which have been implicated in autoimmune disease. Recent studies have revealed that many ligands, both natural and synthetic, can bind efficiently to their NR but do not induce a change in cell activity. I want to understand the reason for this lapse in our understanding of the signalling pathway.

As an approach to solving this problem Dr. Henry Krause’s research group uses zebra fish. This tiny fish has many advantages for biomedical research: they are easy and cheap to maintain, produce hundreds of offspring in a week, have 70% of genes in common with humans, and 84 per cent of genes known to be associated with human disease have a zebrafish counterpart. Zebra fish are transparent, which is very useful for observing effects on internal organs.

Dr. Krause's group has genetically constructed 48 different transgenic zebrafish lines, each carrying one of the 48 known human nuclear receptors and expressing it in their tissues. I will use these to identify ligands that can function only in specific cells or tissues under a variety of physiological conditions. My research will focus on the identification and characterization of such endogenous ligands for orphan NRs in live animals, using the most advanced affinity purification-mass spectrometry approach. This strategy of ligand identification will likely either discover a new class of ligands, or confirm the presence of known endogenous ligands in vivo. Overall, this project will explore the interactions of ligand/NR in physiology/pathology, and shed light on the role of RORs during metabolic and autoimmune disease progression.

Jingwen Song, PhD, McGill University -2017

First observed in 1970 by electron microscopy, gene transcription is the process by which a DNA sequence is copied to make an RNA molecule, which then directs synthesis of the corresponding protein. Transcription consists of three stages: initiation, elongation and termination, which are carried out by a complex called RNA polymerase II (RNA Pol II). In transcription RNA molecules are synthesized as a linear readout of DNA until RNA Pol II encounters signals that tell it to stop, or terminate transcription; at this point the newly synthesized RNA is released from the DNA template. In human cells, transcription termination is a tightly controlled by protein factors associated with RNA Pol II.

Recent advances in cancer biology have revealed that dysregulation of transcription termination can be linked to cancer progression in both mouse and human cells. Abnormal expression of specific termination factors contributes to tumorigenesis. Dr. Jack Greenblatt's group has identified two Pol II-associated factors (RPRD1A and RPRD1B) that likely play a role in transcription termination. RPRD1B is found to be an oncoprotein which is over-expressed in some human cancers. However, the detailed mechanism of how RPRD proteins affect transcription termination in tumorigenesis remains unknown.

My current project is to determine the role of the RPRD proteins in termination of transcription. Working in the laboratory of Dr. Greenblatt, I am developing high-throughput RNA sequencing and gene-knockout screens to study how the RPRD proteins are involved in the regulation of transcription termination, by using both molecular and computational methods. I will also screen for compounds that might affect the termination process and consequently may inhibit cancer cell growth. This study will contribute to the current understanding of the regulatory roles of Pol II-associated proteins, and may have implications and clinical significance for future cancer therapy.

 

 

 

 

 

 

Past Fellowship Holders

2018
Jiabao Liu
Bsc, Harbin University of Commerce, Harbin, China, PhD, Peking Union Medical College, Beijing, China.

2017
Jingwen Song
BSc Henan University of Technology, Henan, China, MSc McGill University, Montreal, Phd McGill University, Montreal

2016
Eugenio Gallo
BSc Purdue University, West Lafayette, MS San Francisco State University, San Francisco, PhD Carnegie Mellon University, Pittsburgh

2015
Marjan Barazandeh
BSc Shahid Beheshti Shahid Beheshti University (Tehran), MSc Tarbiat Modares University (Tehran), PhD University of Alberta

2014
Tim Sterne-Weiler
BS University of California, Santa Cruz, MS University of California, Santa Cruz, PhD University of California, Santa Cruz

2013
Jelena Tomic
PDF - The Donnelly Centre, University of Toronto, ON

2012
Hamed Shateri Najafabadi
Postdoctoral Fellow, University of Toronto

2011
Anna Lee
Bioinformatician - Ontario Institute for Cancer Research, Toronto ON

2010
Jonathan Ellis
Research Associate - The Donnelly Centre, University of Toronto, ON

2009
Lucia Caceres
Research Associate, Dalhousie University

2008
Dewald van Dyk
Research Associate, University of Toronto

2007
Mathieu Gabut
University of Lyon, France

2007
Joseph Barash
Assistant Professor – University of Pennsylvania

2006
Franco Vizeacoumar
Research Associate - Donnelly Centre

2005
Gwenael Badis-Breard
Staff Scientist, Institut Pasteur, France

2004
Gordon Chua
Assistant Professor - University of Calgary

2004
Xianchun Li
Assistant Professor - University of Arizona

2003
Christine Misquitta
Senior Research Associate-Donnelly Centre

2003
Armaity Davierwala
Consultant, Persistent Systems Ltd, India

2002
Gareth Butland
Staff Scientist, Lawrence Berkeley Laboratories USA

2002
Mark Lambermon
Senior QC Analyst, Active BioMaterials, Chicago, IL

2001
Peixiang Wang
Staff Scientist, UHN, Toronto

2001
Ping Yang
Genetic Counselor, Elizabeth Bruyere Centre, Ottawa