Charles H.


"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

Jiaobao Liu, PhD Peking Union Medical College

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

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.

Eugenio Gallo, PhD, Carnegie-Mellon University

Scientific research in the 21st century will deliver tools against medical disorders that previously were impossible or unlikely to treat. One such disease is cancer (which is actually a large group of diseases characterized by abnormal cell growth); statistically one in three people in North America currently are likely to suffer from one or another form of cancer. The direct consequence of unregulated cell growth is the development of tumours that form a mass with the potential to invade or spread to other parts of the body, resulting in death. Tumour masses form unique micro-environments that recruit other non-cancerous cells and blood vasculature, which drive their nutrition, growth, and immune evasion.

Recent advances in cancer biology reveal that a particular family of proteins called integrins are associated with the development and progression of tumours. Integrin proteins are situated in the cell envelope and act as receptors that play a role in interactions with other cells and with the extracellular environment, where they play a pivotal role in cellular behaviour. Integrins regulate cellular activity in two ways. First they mediate the migration of cells by recognizing and attaching to another group of molecules called scaffolds. Second, they act as receptors to regulate signals inside the cell, which influence gene expression and subsequent regulation of cell survival, differentiation and proliferation.

My current research focuses on the study of integrin biology using the latest methods in genetics, and structural, molecular and cellular biology. The main emphasis is to understand the function and roles of different integrins in tumour biology. The second aim, is to develop therapeutic tools and reagents to target specific integrins with the aim of inhibiting tumour growth. Overall, the project offers the potential for the following: the identification and characterization of specific integrins associated with cancer, the development of new antibody tools to study cancer biology, and the generation of biological therapeutics to mitigate tumour development.







Past Fellowship Holders

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

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

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

Hamed Shateri Najafabadi
Postdoctoral Fellow, University of Toronto

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

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

Lucia Caceres
Research Associate, Dalhousie University

Dewald van Dyk
Research Associate, University of Toronto

Mathieu Gabut
University of Lyon, France

Joseph Barash
Assistant Professor – University of Pennsylvania

Franco Vizeacoumar
Research Associate - Donnelly Centre

Gwenael Badis-Breard
Staff Scientist, Institut Pasteur, France

Gordon Chua
Assistant Professor - University of Calgary

Xianchun Li
Assistant Professor - University of Arizona

Christine Misquitta
Senior Research Associate-Donnelly Centre

Armaity Davierwala
Consultant, Persistent Systems Ltd, India

Gareth Butland
Staff Scientist, Lawrence Berkeley Laboratories USA

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

Peixiang Wang
Staff Scientist, UHN, Toronto

Ping Yang
Genetic Counselor, Elizabeth Bruyere Centre, Ottawa