Dr. James GauldChemistry and Biochemistry, University of Windsor
Implications of select TSC2 mutations in cell division and disease progression
Co-Investigators and Collaborators:
- Dr. Lisa Porter, Biological Sciences, University of Windsor
- Dr. Elizabeth Fidalgo da Silva, Biological Sciences, University of Windsor
- Dr. Mohammad Al Sorkhy, Pharmacy, Al Ain University, United Arab Emirates
EVIDENCE OF PROGRESS
A tumour is a mass of cells growing out of control. For a tumour to progress into cancer, it must ensure that it has energy to grow quickly. A normal healthy cell has a central protective mechanism that stops new proteins from being made if nutrients are limited. The main protein controlling this, known as Tuberin, is mutated in a large number of tumour disorders. Many different mutations have been found spanning across the various regions of this very large protein. Some mutations result in small lesions that will never progress to cancer, others result in large tumours that never progress but develop in tissues that are critical to the health of the patient, and still others drive tumour growth that can progress to aggressive malignant cancers. Understanding which mutations are capable of forming cancers will allow physicians to treat patients early and in an aggressive manner that may prevent cancers from forming. Furthermore, determining why these mutations cause cancers will allow for the multiple drugs to be used to block all pathways being affected at once, thereby decreasing the chance of a patient relapsing.
The Gauld chemistry lab at the University of Windsor has teamed up with a lab in United Arab Emirates to adopt a powerful technique of computer modeling here in Windsor that can allow us to predict what proteins look like and how they can interact with other proteins. We are currently making models of the Tuberin protein to predict how mutations affect the function of the protein. The Porter and Fidalgo da Silva cancer biology labs can take this information and test our predictions using tumour cells, including those from patients. To aid in the predictions for our structures they have begun using experiments in the lab to obtain some information about the structure of these proteins. One approach that they have used is to create a system where the proteins will fluoresce when close together – they can change the location of the fluorescent proteins to determine how the proteins are folded in a 3 dimensional shape. They have used this information to make a helpful model to guide the Gauld lab in complex, high resolution modeling.
Over the next year the Gauld lab will complete their computer based models and combine this information with Porter lab results. The Gauld lab will use their information to predict mutations that will prevent interactions with other proteins. The Porter Lab will make these mutations in the protein and validate the change in interaction with other proteins. This work will be very important in understanding how a very important protein in cancer biology can contribute to enhancing cell growth. This information may reveal new mechanisms of targeting this protein using drugs.
MEASURES OF PROGRESS
At present the majority of the results have been obtained through the experimental aspects of this project. Consequently, at present the publications and presentations (see below) that have resulted are primarily of an experimental focus. However, it should be noted that our initial computational homology modeling challenges and results have been informally included as part of larger presentations on my research groups current interests at University of Porto (Portugal) where I held an Erasmus Mundus Master’s Scholar Fellowship during July 2016.
A) Manuscripts and Publications: Two manuscripts are in preparation for submission
B) Conference Presentations: Three conference presentations have been given based on this work: two in Windsor, Canada, and one in Ottawa, Canada
C) Invited Address: Two invited address focusing on Seeds4Hope research were given: one at the University of Windsor, and a second at the University of Ottawa
D) Training of Highly Qualified Personnel:
Research Associate: Dr. Elizabeth Fidalgo da Silva
Senior Undergraduate Students: Marisa Market* and Melanie Grondin
*Marisa Market was awarded the University of Windsor Undergraduate Research Excellence Award 2015, and placed first overall amongst presenters at the Ontario Biology Day Competition.