Subvention catalyseur : Le sexe comme variable dans la recherche biomédicale ou translationelle
Le subvention catalyseur : Le sexe comme variable dans la recherche biomédicale ou translationelle de l’Institut de la santé des femmes et des hommes a pour but d’encourager les chercheurs dans le domaine biomédical à tenir compte du sexe comme variable dans leurs questions de recherche et dans leurs plans expérimentaux.
Depuis le début des années 2000, la communauté de recherche reconnaît de plus en plus que le sexe des cellules, des tissus, des animaux et des humains compte dans la recherche biomédicale et translationnelle. Chaque cellule est sexuée, et les différences sexuelles s’observent dès la conception et varient tout au long de la vie.
La prise en considération du sexe favorise la reproductibilité des conclusions de la recherche et accroît la rigueur scientifique en rendant les résultats plus généralisables aux hommes et aux femmes. Lorsque le sexe n’est pas pris en compte, des effets importants peuvent passer inaperçus.
Les objectifs particuliers de cette possibilité de financement sont les suivants :
- Rehausser l’état actuel des connaissances biomédicales de base sur un sujet donné qui offre la possibilité d’élucider – sans avoir permis de le faire entièrement encore – l’impact du sexe ou du genre sur les mécanismes biologiques, la pathophysiologie ou la science translationnelle.
- Contribuer à l’amélioration de la santé des femmes et des hommes au Canada et dans le monde, ainsi qu’à la création de services et de produits de santé plus efficaces et adaptés au genre.
Le montant total disponible dans le cadre de cette possibilité de financement est de 2 100 000 $, ce qui devrait permettre d’accorder 14 subventions pour une période maximale de 2 années.Consulter la liste complète des boursiers et les résumés de leurs projets de recherche
Boursiers [Résumés en anglais seulement]
Sex Differences in Somatic Mutation Profiles: A Pan-Cancer Assessment
Dr Paul Boutros, Ontario Institute for Cancer Research (Toronto, ON)
Abstract: It has been known for decades that cancer occurs differently in men and women. On average, men are more likely to be diagnosed with cancer than women -- even after adjusting for differences in lifestyle like smoking and occupation. Many tumour types show striking asymmetry in incidence rates: for example, thyroid cancer occurs ~2.5 times more frequently in women than men. Further, men and women often respond differently to therapy, with women often responding better to surgery and chemotherapy than men. Surprisingly, the origin of these differences remains largely unknown. One candidate explanation is that the mutagenic processes that damage DNA to cause cancer do so in different ways in men and women. We propose to exploit two recently-developed, large, multi-national dataset of tumour genome sequences. We will study 20 different cancer types, and for each specifically compare the mutations occurring in tumours of men and in tumours of women using statistical and computational techniques to understand if there are recurrent differences between them. To date, preliminary analyses suggest that there are substantial genetic differences in tumours between the sexes. This work has the potential to transform the way cancer is researched by placing increased focus on the sex of model systems used, as well as to greatly influence the application of targeted therapies which may be differentially effective between the sexes.
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Toward a clinically applicable characterization of sex differences in biological aging
Dr Alan A. Cohen, Université de Sherbrooke (Sherbrooke, QC)
Dr Tamas Fulop, Université de Sherbrooke (Sherbrooke, QC)
Abstract: We have long known that women live longer than men, and that the biological aging process differs between the sexes, not just in humans, but in many animals. However, we have very little understanding of why women age more slowly, nor what this means for treating patients in a sex-appropriate way as they age. Recent research in our lab suggests a way forward: we have developed the first reliable way to measure "physiological dysregulation," the way that our bodies slowly lose the ability to control the many functions necessary to sustain life. We have shown that physiological dysregulation changes differently with age in men and women. Here, we propose to study in detail how physiological dysregulation happens in men and women. Does the immune system become dysregulated faster in one sex than the other? Do changes in certain types of dysregulation increase the risk of chronic diseases more in one sex than the other? The answers to questions such as these will paint a portrait of the aging process in each sex, and suggest clinical directions that will tailor treatment of aging patients to the way their sex ages. To do this, we use innovative statistical methods we developed applied to large datasets of biomarkers (cholesterol, blood sugar, anemia, etc.) followed over time in thousands of patients. We will also confirm our results in seven primate species in order to establish how biologically universal any differences are. These results will advance fundamental biological knowledge of how aging differs between the sexes, and will also create a foundation for clinical interventions.
Chemical-induced gender specific hepatic cancer: a rodent model for understanding gender specific effects
Dr Daniel G. Cyr, INRS (Quebec, QC)
Dre Isabelle Plante, INRS (Quebec, QC)
Abstract: Environmental carcinogens, such as hexachlorobenzene (HCB), can predispose females to develop liver tumors. This effect is associated with a loss in gap junctional communication only in female rats, males are unaffected. Gap junctions allow intercellular communication between adjacent cells and are formed by proteins referred to as connexins (Cx). In the liver there are two predominant connexins that are expressed: Cx32 and Cx26. We have shown that the female rats express almost 10 times less Cx32 than males while they express more Cx26 than their male counterparts. The lower levels of Cx32, in part, render females more susceptible to HCB-induced precancerous state. In the present proposal we wish to determine at what age rats develop the sexual dimorphism of Cx32/Cx26 expression and if gender specific HCB-effects can be mediated prior to the gender dependent dimorphism in connexins expression. Furthermore, we intend to determine the mechanism responsible for the sexual dimorphism of connexins in the liver as this lay the foundation for understanding male-female differences in response to organochlorine carcinogens.”
Adiponectin Receptor paThway as a key playEr in carotid atheroscleRotic plaque instabilitY: what has sex got to do with it? (ARTERY)
Dr Styliani Daskalopoulou, Research Institute of the McGill University Health Centre (Montreal, QC)
Dr Jean-Francois Cailhier, Research Institute of the McGill University Health Centre (Montreal, QC)
Dr Robert B. Cote, Research Institute of the McGill University Health Centre (Montreal, QC)
Dr Ciriaco A. Piccirillo, Research Institute of the McGill University Health Centre (Montreal, QC)
Dr Elham Rahme, Research Institute of the McGill University Health Centre (Montreal, QC)
Dr Francis Rodier, Research Institute of the McGill University Health Centre (Montreal, QC)
Abstract: Every 10 minutes a Canadian suffers a stroke. Stroke kills more women than men each year. They are mainly caused by the build-up of fatty deposits (plaques) in the arteries of the neck, that can break-off and travel to the brain. We only know for sure if a plaque is dangerous when it is removed by surgery and assessed under the microscope. Often this is too late as the patient may have already suffered a stroke. It is known that men have more dangerous plaques than women. Thus, research is necessary to understand the different mechanisms that lead to dangerous plaques in women and men. Current knowledge: 1.Some cells in plaques, called macrophages (Mfs), can make the plaque more dangerous. Mfs come from cells in the blood called monocytes. When monocytes enter the plaque, they become Mfs. 2.Adiponectin is a substance in the body that may protect our arteries from developing dangerous plaques. To work, adiponectin is like a key that must attach to its lock on a cell (monocyte or macrophage). Those locks are called receptors. Defects in these receptors may cause dangerous plaques. Research objectives: 1.Assess if women and men have differences in adiponectin receptors on their monocytes and Mfs when they have either dangerous or harmless plaques. 2.Assess if women and men have different defects in the adiponectin receptors on monocytes and Mfs that make plaques more dangerous. Undertake: We will include women and men having a surgery to remove the plaques (dangerous or harmless) from their neck arteries. We will use advanced lab methods to address our research objectives. Impact: ARTERY will identify differences between women and men in adiponectin receptors and if these differences lead to more or less dangerous plaques. In the future, our study may help us find markers to predict dangerous plaques, and new targets for therapy, leading to better care specifically designed for women and for men. Ultimately, this could prevent strokes and save many lives!
The impact of sex on FGF21 in the pathogenesis and treatment of the metabolic syndrome
Dr Jennifer Estall, Institut de recherches cliniques de Montréal
Dr Aurèle Besse-Patin, Institut de recherches cliniques de Montréal
Abstract: Metabolic diseases affect millions of men and women in North America. Obesity and Type 2 diabetes will likely affect one third of the population by 2050. Men and women develop metabolic disease in different ways, and women are more protected from metabolic diseases until menopause, suggesting important difference in physiology due to sex. However, scientific studies required for new treatments to be approved for use in humans (i.e. how a drug works and how well it works) are mainly done in only males (animals and people). This practice in early phases of testing prevents us from knowing whether males versus females could respond differently. FGF21 is one new therapeutic target currently being tested for its ability to treat a variety of metabolic diseases, due to its impressive benefits on cardiovascular, liver and fat metabolism in male mice and humans. However, FGF21 biology in females is virtually uncharacterized. We will investigate and directly compare sex-specific responses to FGF21 in models of obesity and liver disease caused by poor diet. This research will provide a better framework as to whether FGF21 is an effective drug to treat metabolic disease in both men and women.
Increased risk of cardiovascular disease in women with inherited chromosomally-integrated human herpesvirus 6
Dr Louis Flamand, Centre hospitalier de l’Université Laval (Quebec)
Dr Marie-Pierre Dubé, Centre hospitalier de l’Université Laval (Quebec)
Dr Jean-Claude Tardif, Centre hospitalier de l’Université Laval (Quebec)
Abstract: Cardiovascular diseases (CVD) represent a major health concern. Although some of the risk factors contributing to CVD are known, such as high blood pressure, high cholesterol levels and smoking, others remains to be identified. After analyzing samples from 20,000 Quebecers, we noticed that individuals that carry a virus (human herpesvirus 6 also known as HHV-6) inserted into their DNA are 3X more likely to develop angina. When we looked for association with sex, women were more at risk of angina than women without this condition or men. Our primary objective is to validate and extend these results by screening the Montreal Heart Institute (MHI) biobank (n=20,000). In addition, we propose a series of experiments to better understand why women with chromosomally-integrated HHV-6 are at greater risk if cardiovascular disease development.
Effect of exercise intervention on brain health in older age: interaction between sex and genotype
Dre Liisa A. Galea, University of British Columbia (Vancouver, BC)
Dre Cindy Barha, University of British Columbia (Vancouver, BC)
Dre Teresa Y. Liu-Ambrose, University of British Columbia (Vancouver, BC)
Abstract: Dementia is one of the most pressing health care issues of the 21st century and no effective drug treatment exists. However, exercise can reduce memory decline and may be an effective treatment for dementia. Importantly, studies suggest that older women benefit more from exercise than men. To harness exercise's ability to combat dementia it is vital to discover why women show greater beneficial effects of exercise on brain health. Women are also more likely to be diagnosed with Alzheimer's Disease (AD), irrespective of the fact that they live longer than men. Half of older people diagnosed with Mild Cognitive Impairment (MCI) will transition into AD and women progress from MCI to AD at a faster rate than men. Thus factors that reduce the conversion of MCI to AD are sought after and exercise is one such factor. Our research aims to understand the mechanisms behind the ability of exercise to ameliorate cognitive decline more in women with MCI compared to men with MCI. We will examine how biological sex coupled with stress, inflammation and hormones are altered after exercise and whether genetic differences contribute to the effects of exercise to promote memory. We will focus on one particular protein called brain derived neurotrophic factor (BDNF), which is involved in brain health and is a mediator of the cognitive-enhancing effects of exercise. Importantly, there is an alteration within the BDNF gene is some humans that alters the levels of this protein. This alteration in BDNF may influence exercise's ability to promote brain health in women more so than men. We will use clinical and preclinical models to examine the effects of sex, genetics and hormones on the ability of exercise to influence brain structure and memory. Although sex differences exist in AD, research targeting sex as a factor is scarce. Our program will be vital in filling this knowledge gap and will foster the development of tailored, personalized treatments for cognitive decline in both sexes.
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SexImmunome of Virus-assisted Cancer Immunotherapy: Discovery, Characterization and Therapeutic Implications
Dr Patrick W. Lee, Dalhousie University (Nova Scotia)
Dr Shashi A. Gujar, Dalhousie University (Nova Scotia)
Abstract: Similar to what you would read in sci-fi novels, viruses can be used to treat human malignancies. On October 27, 2015, the US Food and Drug Administration (FDA) approved the use of herpes virus (trade name Imlygic) for the treatment of skin cancer. This first-of-a-kind historic decision is set to accelerate the already fast-paced research and development efforts around similar type of therapeutics. These cancer-killing viruses, known as oncolytic viruses (OVs), act through two distinct mechanisms: 1) kill cancer cells directly, and 2) educate patient's immune system to attack cancer on its own. It is now clear that these virus-driven anti-tumor immune responses are the indispensable part of this therapy. Currently, many viruses are being tested in clinical trials worldwide for the treatment of cancers of almost every origin. These virus-assisted cancer immunotherapies (VaCIs) are believed to be one of the most promising cancer treatments of the modern era. Interestingly, no preclinical research to this date has investigated the impact of sex on VaCIs. Unfortunately, these findings from preclinical research done without considering sex as a variable get further extended in clinical settings and continue to be applied in a generalized fashion between sexes. It is now evident that these practices form the basis of differential therapeutic efficacies/toxicities between males and females. Evidence suggests that sex influences host immune responses, especially in the context of virus infection and cancer patho-physiology. This evidence has led to the hypothesis that sex-biased differences must exist between males and females during VaCIs. Hence, the overarching goal of this preclinical research project is to first understand the sex-biased immunological differences (collectively designated as SexImmunome), and then define their impact on the efficacy of virus-based cancer immunotherapy.
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Sex differences in NETosis: effects on infection and inflammation in children
Dr Nades Palaniyar, Hospital for Sick Children (Toronto)
Dr Colin Mckerlie, Hospital for Sick Children (Toronto)
Dr Neil B. Sweezey, Hospital for Sick Children (Toronto)
Abstract: Females and males respond differently to many diseases. Sex hormones cause different immune responses in boys and girls, before and after puberty. In general, females are better at making a strong immune response against acute infections. However, they suffer more from chronic infections and inflammatory diseases, as well as from autoimmune diseases (where the immune system attacks its own body). In these cases, the female immune responses can be excessive, making the disease worse than in males. Neutrophils are key, first line, innate immune defense cells that migrate into lungs and other organs when the organs are infected. In the presence of bacteria, the neutrophils can generate toxic neutrophil extracellular traps (NETs) that trap and kill bacteria. This process (NETosis) is good for killing germs during acute infections, but the presence of a lot of NETs for a long time can worsen inflammation, increasing tissue damage. Therefore, NETs could be a major reason that chronic inflammation is often worse in females than in males. We propose to determine the effects of female and male sex hormones on NETosis in boys and girls, before and after puberty. We will use mice to study how these hormonal effects come about. This information is expected to provide a foundation to understand inflammatory diseases in females, and to design therapies to improve the health of people with lung diseases that have too much NETosis.
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Sex and the Ageing Heart: The molecular basis for the functional decline and development of a novel therapeutic target
Dr Glen Pyle, University of Guelph
Abstract: Females have lower rates of heart failure compared to age-matched males throughout most of their life. However, after menopause the risk for heart failure in women rises until the difference between the sexes disappears by age 80. Ageing itself in an independent risk factor for heart failure and with populations throughout the world seeing significant increases in older demographics it is expected that the rates of heart failure will rise dramatically. Why pre-menopausal women are relatively protected against heart failure compared to age-matched men is unknown, as is the reason for the loss of protection after menopause. It has been speculated that estrogens contribute to the protection against heart failure, but the molecular mechanisms that mediate this effect remain unidentified. We have shown that hearts from aged male mice exhibit significant increases in the level of an actin binding protein called 'CapZ'. This decrease corresponds with a reduction in heart function. Interestingly, age-matched female mice show a reduction in CapZ protein in the heart along with normal heart function. Mice of both sexes that are engineered to have reduced levels of CapZ in the heart show no decline in heart function with ageing. We hypothesize that female mice decrease CapZ levels in the heart to protect against age-dependent cardiac dysfunction, whereas male mice are unable to do so. Our programme will determine how sex influences cardiac function in ageing mice, and assess the impact of sex and ageing on cardiac CapZ levels. We will also investigate CapZ regulatory elements including CapZIP, Hsc70 and BAG3 to determine if these factors play sex-dependent roles in CapZ regulation in the ageing heart. This research will advance our understanding of the influence sex mediates over heart function, identify the molecular basis for sex-dependent cardiac dysfunction in ageing mice, and establish the therapeutic potential of reducing CapZ to block cardiac decline and extend life.
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Investigating sex-specific differences in a T cell-driven mouse model of MS
Dr Manu Rangachari, Centre hospitalier de l’Université Laval (Quebec)
Abstract: Multiple sclerosis (MS) is a progressive, degenerative disease of the central nervous system in which the body's immune system attacks the insulating sheath ("myelin") that surrounds nerves. Canada has one of the highest rates of MS incidence in the world. Women are up to 3 times as more likely as men to develop MS, and thus it is crucial that we better understand the role that an individual's sex plays in developing this disease. In this project, our hypothesis is that differences between the sexes in the function of a specific immune cell type, the T cell, can help explain why females are more prone to MS. Using genetically engineered mice, we will separately examine the ability of male or female T cells to cause an MS-like disease. Then, using a cutting-edge technology known as "mass cytometry", we will identify the molecular pathways that are responsible for these differences. We aim to identify mechanisms that explain female susceptibility to MS, with the ultimate goal of developing better and more effective therapies.
The sex/tissue-specific regulation of the LDLR in absence of PCSK9 activity and its clinical relevance
Dr Nabil G. Seidah, Institut de recherches cliniques de Montréal (Montréal, QC)
Dre Annik Prat, Institut de recherches cliniques de Montréal (Montréal, QC)
Abstract: We discovered a family of 9 enzymes, the proprotein convertases (PCs), which are involved in producing the final forms of active proteins, and are world leaders in understanding their roles in pathologies, especially that of PCSK9 in cardiovascular diseases. PCSK9 reduces the levels of the LDLR, the clearance receptor of the bad LDL-cholesterol (LDLc), and hence too much of this enzyme results in high levels of LDLc in the blood, which are associated with coronary heart disease. PCSK9 is one of the most promising targets in medicine today, in large part thanks to our pioneering work on this protein. Until recently, it was thought that the activity of PCSK9 on LDLR is sex-independent. Using mice lacking PCSK9 (KO mice), we were the first to report that PCSK9 deficiency unmasks a sex/tissue-specific cellular localization of the LDLR, leading to reduced cell surface levels (and hence bioavailability to LDLc) in the liver of female compared to male PCSK9 KO mice. This results in a lower efficacy of LDLc clearance from the blood in female mice lacking PCSK9. New injectable treatments using a monoclonal antibody (mAb) against PCSK9 have just been accepted by the health authorities to effectively lower LDLc by 60% in hypercholesterolemic patients. Our work and a Sanofi report on the efficacy of the mAb treatment in human, pointed out a sex- and tissue-specific difference in the response to PCSK9 inhibitors, with female mice/pre-menopausal women being less responsive than males/men. Our 2-year research program will concentrate on identifying the mechanism behind the estrogen regulation of the functional activity of LDLR in the liver, under conditions where PCSK9 is either absent or low, as is the case in PCSK9 KO mice or in humans treated with a monoclonal antibody (mAb) to PCSK9. The outcome of this research will have a direct translational implication in cardiovascular clinics, especially for pre-menopausal women undergoing cholesterol-lowering therapy against PCSK9.
Personalizing Inhaler Therapy For Men and Women With Chronic Obstructive Pulmonary Disease (COPD)
Dr Donald Sin, St. Paul’s Hospital (Vancouver, BC)
Dr Patricia G. Camp, St. Paul’s Hospital (Vancouver, BC)
Dr Ma’en Obeidat, St. Paul’s Hospital (Vancouver, BC)
Dr Peter D. Pare, St. Paul’s Hospital (Vancouver, BC)
Abstract: Chronic obstructive pulmonary disease (COPD), formerly called emphysema, chronic bronchitis, asthmatic bronchitis and smokers' lung, affects 1 in 10 Canadians over the age of 40. COPD is the number one reason why Canadians require hospitalization and re-hospitalizations. Inhalers to open up breathing tubes and reduce inflammation in the lungs are the most commonly prescribed medications for patients with COPD. However, all of these drugs were developed in clinical studies that recruited >70% men. Women have smaller lungs and may have more disease in the breathing tubes, so they are likely to have different responses to these inhalers. In this project, we will first determine whether women indeed have greater burden of COPD than men; then, we will determine whether inhaler therapy is more or less effective in women than in men and finally, because these drugs only work well in less than half of patients who take them, we will find out based on genetics which men and women will derive the most benefits (and least side effects) of these inhalers.
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Adult neurogenesis and memory generalization in males and females
Dr Jason S. Snyder, University of British Columbia (Vancouver, BC)
Abstract: Anxiety disorders are one of the most widespread mental health disorders and affect significantly more women than men. They are associated with tension, sleep loss, irritability and unnecessary fear. Unfortunately, the causes of anxiety disorders, particularly the sex differences in vulnerability, are still poorly understood. Many types of anxiety have in common an increased tendency for environmental cues to trigger fearful behaviors. These cues are more likely to remind people of a previously traumatic experience, leading them to frequently become anxious and fearful about subsequent encounters. One approach for studying and potentially treating anxiety disorders therefore involves memory. The hope is that if memories can be made more specific and detailed then they can be more effectively compared the current situation. This could reduce the fear of situations that may partially resemble a previous bad experience, but are still different enough that they should not be feared. One of the most exciting recent discoveries in neuroscience is the ongoing production of new neurons throughout adult life. Thousands of new neurons are added each day to the human hippocampus, a structure involved in memory formation. Animal models have shown that these newborn neurons are particularly important for highly detailed memory formation. This suggests that they may be important for minimizing the generalized fear that is observed in anxiety disorders. However, a major limitation of these studies is the near complete absence of female subjects. Since women are more likely to suffer from anxiety disorders, the goal of this research is to identify the cellular and behavioral functions of newborn neurons in females as compared to males. These findings will speak to the mechanisms by which memory circuits might be targeted for treating anxiety disorders, and they will hopefully open the door to studies of neurogenesis function in females in addition to males.
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Mechanisms of Sex Differences in Focal Cerebral Ischemia
Dr Bojana Stefanovic, Sunnybrook Research Institute (Toronto, ON)
Dr Peter L. Carlen, Sunnybrook Research Institute (Toronto, ON)
Abstract: Neurons and brain blood vessels work in concert so that blood flow increases when neurons become active. This neurovascular coupling is compromised in stroke, whereby a blockage of a major artery results in a sharp decline in blood flow, causing damage to the neurons, and inducing sudden paralysis, impaired speech, and/or loss of vision. If the blood clot is dissolved rapidly, the likelihood of a complete recovery is very good. However, due to the very narrow time window (3-4.5 hours) for safe and effective dissolution of the clots, only ~2% of patients receive these drugs; most suffer significant disabilities, and up to a third are institutionalized. Furthermore, while premenopausal women have far fewer strokes than men of the same age; post-menopause, women suffer greater post-stroke disability than do men. A major factor preventing the development of more effective therapies is the uncertainty surrounding the cellular changes needed for full recovery of brain function, particularly in the peri-infarct zone, the impaired, but potentially salvageable brain region adjacent to the area directly affected by the loss of blood supply. The goal of the present proposal is to understand the changes in the neurovascular coupling in the peri-infarct zone in the weeks following stroke in women vs. men. This work will be conducted using advanced 3D imaging post stroke in live male rats, premenopausal female rats, and postmenopausal female rats administered either placebo or put on estrogen replacement therapy. The neurons and blood vessel functioning will be contrasted between untreated animals and those treated with a compound that provides an alternate source of energy to the brain. These experiments will interrogate the mechanisms by which changes in the neurons and blood vessels support rehabilitation as a function of sex and estrogen levels and thereby guide the development of new treatments that may be applied in the chronic stage following stroke in both sexes.
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Profound sex differences in a sub-strain of Sprague-Dawley rats exhibiting genetically determined hyper-responsiveness to VEGFR2 inhibition causing severe pulmonary arterial hypertension
Dr Duncan J. Stewart, Ottawa Hospital Research Institute (Ottawa, ON)
Dr Ketul R. Chaudhary, Ottawa Hospital Research Institute (Ottawa, ON)
Abstract: Pulmonary arterial hypertension (PAH) is a disease of narrowing or loss of lung blood vessels causing high blood pressure in the lungs and the right side of the heart. This leads to enlargement of the right side of the heart, heart failure and ultimately death. While recent developments have improved the quality of life and increased the survival time, there is no cure for this devastating disease. It is also not clear what causes this disease and how it progresses. Some genetic defects have been linked to PAH but a big portion of the cases remains unexplained. Moreover, PAH affects more female than males but female patients have better survival than males. In the animal models, majority of studies have reported protective effects of estrogens against PAH. Therefore, the role of female sex hormones in PAH is not clearly understood. In the animal model of PAH, we have observed that less female rats develop this disease than male rats, may be due to protective effects of female sex hormones. Therefore, in the proposed project, we will also investigate the effects of sex hormones in PAH. In addition, we believe that the female sex hormones are protective but the periodic withdrawal of this protective signal in female makes them susceptible to developing this disease. No study has been performed yet to investigate the effects of cyclic changes in female sex hormones on PAH. We will study the effect of changes in female sex hormones on development of PAH in PAH susceptible rat strain. We will also investigate the effect of periodic changes in female sex hormones on cell derived from susceptible and non-susceptible rats. In addition, we will perform similar experiment using the PAH patient derived endothelial cells. This work will improve our understanding of PAH and could provide novel targets for developing therapies for this incurable disease.
Gender differences in innate lymphoid cells and asthma
Dr Fumio Takei, B.C. Cancer Research Centre (Vancouver, BC)
Abstract: Asthma is one of the most common health problems in Canada. Many studies have found that adult women are more likely to develop asthma than adult men, but the precise reason for the gender difference in asthma incidence is currently unknown. Asthma is caused by over-production of a group of proteins called type 2 cytokines that induce excessive mucus production and narrowing of airway, which result in breathing difficulty. We have found a family of innate lymphocytes called ILC2 that produces large amounts of type 2 cytokines. We have also found that asthma risk gene called Rora regulates ILC2. Studies on the Rora gene by other groups have found that sex hormones may regulate the gene. Therefore, we think female sex hormones act on the Rora gene and increase the number of ILC2, resulting in more type 2 cytokine production and asthma development. We will test this idea by comparing the numbers of ILC2 and the expression the Rora gene in male and female mice. We will also test the effects of sex hormones on ILC2 in cultures as well as asthma development in mice. Through this study, we hope to find out why adult women are more likely to get asthma than men. This study may result in new ways to treat asthma patients.
X-chromosome wide genetic association on cancer prognostic and pharmacogenetic analysis of clinical trials: methodological development and analysis
Dr Wei Xu, University Health Network (Toronto, ON)
Dr Geoffrey Liu, University Health Network (Toronto, ON)
Dr Bingshu E. Chen, University Health Network (Toronto, ON)
Dr Rayjean Hung, University Health Network (Toronto, ON)
Dre Helen J. Mackay, University Health Network (Toronto, ON)
Dr Christopher O’Callaghan, University Health Network (Toronto, ON)
Dr Dongsheng Tu, University Health Network (Toronto, ON)
Abstract: Response and toxicity to cancer drug therapy and radiation varies from person to person. Pharmacogenetics is the study of the genetic effects on drugs response and toxicity. We also know that in some instances, women and men have different responses to therapy and/or different side effects to the treatment. Advances in genetics now allow us to evaluate hundreds of thousands of genetic variations in our DNA. Analyses have discovered how some hormones are less effective in breast cancer treatment in some individuals, and how some patients develop severe side effects to the heart or to hearing when given specific chemotherapeutic drugs. Yet, one area that has not been studied well has been the genetic variation in the X and Y chromosomes, the sex chromosomes that define whether we are male or female biologically. A reason for this has been the fact that the analysis of these sex chromosomes is more complex than with other chromosomes. Statistical tools have not been developed for rapid analysis, particularly when dealing with survival analysis - the analysis of how long someone lives after diagnosis with a cancer, a critical cancer treatment outcome. Our primary goal aim is to develop such methods (Aims 1 and 2), and apply them to pharmacogenetic analysis of clinical trials (Aim 3) where we already have unanalyzed genetic data on the X chromosomes, and carefully collected clinical information to answer clinically relevant questions related to genetic factors affecting survival and toxicity. Our research team involves a NCIC clinical trials group team (Drs. O'Callaghan, Chen, Tu), a methodological statistician (Dr Xu, nominated PI) who has performed genetic analysis on these clinical trials, the pharmacogenetic senior scientist (Dr. Liu, co-PI), a second content expert on GWAS methodologies (Dr. Hung), and another expert on trials (Dr. Mackay). Together we will develop new methods of analysis and apply them immediately for translational research.
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