Preclinical testing of novel kinase inhibitors for ovarian cancer control
In Canada, every 3.5 hours a woman is diagnosed with epithelial ovarian cancer (EOC) and they have an approximately 45% chance of surviving 5 years or greater. Around 2600 Canadian women per year are diagnosed with EOC, and ~1600 deaths are attributable to the disease. Specifically in Manitoba we have on average 93 women per year diagnosed. The major factors contributing to this high mortality rate are the late stage of the disease when it is diagnosed and the development of recurrent, chemotherapy-resistant disease in ~75% of all patients. A major breakthrough for the field would be the development of novel therapeutics to combat inherent and acquired chemotherapy resistance. To give context for the present application, we examined the effect of kinase inhibitors as part of our program of research investigating the EOC microenvironment, and specifically the role of autocrine bone morphogenetic protein (BMP) signalling. My laboratory discovered that autocrine BMP signalling enhances EOC cell motility and invasion, but does not affect cell proliferation. The two kinase inhibitors we tested effectively block BMP signalling. We discovered that these related kinase inhibitors produce a dose-dependent cytostasis or cell death, respectively, in primary human EOC cells. The purpose of the present application is to make a more in-depth examination of the mechanism of action and efficacy of these drugs on EOC cell biology and tumour burden in vitro and in vivo. We hypothesize that the use of these kinase inhibitors may be useful as novel adjuvant agents to treat EOC. The objectives of this research project are to (1)evaluate drug sensitivity and mechanism of action using monolayer and 3D EOCcell models, and (2) test drug efficacy in vivo using an EOC xenograft models of chemoresistance.
Department Investigator(s): Dr. Mark Nachtigal (PI)
Funding Agency: MHRC (Year 1 - $74 257; Year 2 - $80 823)
A Twin Study on the relationship between autism spectrum disorders and perinatal and comorbid conditions
Autism spectrum disorders (ASD) have been extensively studied to determine the genetic, epigenetic, and environmental risk factors that may be involved as well as the possible associations between these disorders and other conditions. This study examined the association btween perinatal factors and ASD and between the comorbidity of ASD with congenital and other mental and behavioural conditions, using a twin study model. Fifteen twins affected with ASD were identified through chart review at the Child Development Clinic (CDC) of the Children's Hospital. The chart review revealed that 4 of the 6 same-sex twin pairs were condordant for ASD and 1 pair was discordant. In addition, we identified 67 twin pairs with at least one ASD affected twin through the Data Respository at the Manitoba Centre for Health Policy. Association tests were conducted between ASD and perinatal, congenital, and mental and behavioural conditions. Test results revealed that there was a significant association between ASD and other mental behavioural conditions (p=0.03; OR 2.27; 95% CI 1.08-4.78). Significant results were also found for comorbidity of ASD with developmental delays (p=0.02; OR 2.88; 95% CU 1.19-5.07). Future directions of this project will involved using only discordant monozygotic twins to examine the effect of epigenetic factors on ASD.
Department Investigator(s): Dr. Michelle Liu (PI)
Funding Agency: Internal Funds, University of Manitoba - $10,000
Depending on the time of the splitting after fertilization, monozygotic twins (MZ) could have one common chorion (Monochorionic, MC) if the splitting happens during days 4 to 8, or separate chorions (dichoronic, DC) if the splitting happens during days 1 to 3. Many studies have been conducted to compare the phenotypes from the MC and DC MZ twins. However, the results are inconclusive. Recently, Kaminsky et al. (2009) compared the DNA methylation profiles from 12K CpG sites using MC and DC MZ twins as well as dizygotic twins (DZ) and found that the DC MZ twins had more similar DNA methylation profiles than the DZ twins while the MC MZ twins were not different from the DZ twins.
We hypothesize that during the re-establishment of a new epigenetic profile in early embryonic developmetn, the epigenetic similarity of MZ twins in certain tissues is determined by the timing of the splitting of the embryonic cells; e.g. MZ twins may have more similar epigenetic profiles if the separation happens earlier during development. There are two specific aims in this study: 1) To recruit and identify the MC MZ, DC MZ, and same-sex DZ twins. 2) To investigate the genome-wide DNA methylation differences among the MC MZ, and DZ twins.
One hundred and fifty mothers with twin pregnancy will be recruited from two hospitals in Winnipeg. Buccal swab samples will be collected from ~100 same-sex twin pairs and 48 of them, including 16 MC MZ, 16 DC MZ, and 16 DZ twins will be used for DNA methylation with the Illumina Human Methylation450 BeadChip. The DNA methylation profiles will be compared among the MC MZ, DC MZ, and DZ twins
This study will provide the baseline DNA methylation profiles for newborn twins and insights on the effects of early human embryonic development on epigenetic features. Furthermore, it will provide guidelines for future studies using discordant MZ twins to investigate the relationship between epigenetics and diseases. Epigenetic modifications are more dynamic than genetic variants and have the potential to be better targets for disease treatment and prevention.
Department Investigator(s): Dr. Michelle Liu (PI); Dr. Jennifer Hunt (Co-I)
Funding Agency: Manitoba Medical Service Foundation
University Research Grants Program
Internal Funds, University of Manitoba
Hysteroscopy in a procedure compared to the operating room
Department Investigator(s): Shauna Leeson, RN (PI); Dr. R. Boroditsky (Co-I)
Funding Agency: CIARE Summer Research Project
A feasibility study for The Manitoba Twin Registry: A Resource for Genetic and Epigenetic Studies
We hypothesize that because of the characteristics of twins, genetic and epigenetic studies using twins will enhance our ability to understand the relationships between epigenetic changes and human diseases and betwen genetic variants and epigenetic variation. We propse a feasibility study to (1) identify all the twins born in Manitoba between 1979 and 2010 using the Manitoba Population Health Research Data Repository: (2) identify healthy twins and the same sex twins, who are discordant for a selected group of diseases for future genetic and epigenetic studies.
Department Investigator(s): Dr. Michelle Liu (PI)
Funding Agency: Startup Funds, University of Manitoba
Population-based linkage analysis for autism spectrum disorders
The objective of this proposal is to identify genetic loci that are in linkage with autism spectrum disorders and their related phenotypes. We hypothesize that there are many rare variants underlying the genetic architecture of ASD. In order to detect the location of these rare risk variants, we propose to perform a genome-wide population-based (in contrast to family-based) linkage study which can identify excess identity-by-descent sharing segments.
Department Investigator(s): Dr. Michelle Liu (PI)
Funding Agency: Autism Speaks
Normal human pregnancy results in significant changes to maternal physiology. These physiologic changes are progressive and are required for support and protection of the developing fetus and in preparing the mother for parturition. The cardiovascular system undergoes substantial alterations during the course of pregnancy, from shortly after conception, until several months postpartum. In the postpartum period, reversal of the adaptations made during pregnancy need to occur. These take place up to 24 weeks postpartum, with most occurring fairly soon after delivery. Structural and functional changes that develop during pregnancy have previously been investigated by numerous methods, and echocardiography currently remains the standard modality. To our knowledge, there have been no published reports of the use of cardiac MRI to assess cardiac function and structural change during normal, healthy pregnancies and postpartum. Establishing baseline structural and hemodynamic changes for normal pregnancies is of benefit in interpreting abnormal changes seen in maternal cardiac disease states, as well as in assessment of patients with underlying cardiac disease in terms of expected functional or structural alterations during the course of pregnancy.
Department Investigator(s): Dr. Michael Helewa (Co-I)
Funding Agency: Canadian Foundation for Women's Health