Published in Dalhousie News on Feb 06, 2018.
Eight medical scientists from Dalhousie University are the recipients of over $5 million in funding from the Government of Canada for their innovative health research.
Three clinician scientists affiliated with the medical school and Nova Scotia Health Authority also received funding, bringing the total in new health research funding to $7.7 million.
The funding, which is provided by the Canadian Institutes of Health Research (CIHR) project grants, will help Dal’s world-class researchers study a wide range of topics, including: cancer therapy and gene editing; low testosterone and its impact on the heart; pharmaceutical safety and transparency; insulin resistance and heart muscle damage; neurodevelopmental disorders; innate immune memory; more effective breast cancer treatments; and alternative therapies for bacterial infections.
“Our government is fully committed to taking concrete action when it comes to the health and well-being of all Canadians,” said The Honourable Ginette Petitpas Taylor, Minister of Health, in a news release. “This investment will fund research that will lead to new treatments, breakthroughs, and fundamental advances in health science. We are proud of our researchers, and will continue to support them in their efforts to help keep Canadians healthy and continue their research right here at home.”
The Project Grant competition is one of CIHR’s flagship funding programs. Project grants are multi-year grants designed to support researchers at various stages in their careers as they conduct health research and knowledge translation projects that cover the full range of health research topics. Project grant recipients are leaders in their fields and their projects tackle pressing health issues that matter to Canadians, such as cancer, autism, heart disease, and dementia.
“We are proud of the remarkable work being done by our medical researchers, who are improving health and helping us all live healthier lives,” says Alice Aiken, vice-president research for Dalhousie. “We are incredibly grateful for the support they are receiving from CIHR, which enables them to continue leading the way in developing innovative solutions to today’s most pressing health care problems.”
The announcement was made on Wednesday, January 24 at Memorial University of Newfoundland. In total, 512 research projects from across the country will receive $372 million in funding.
Highlights of successfully funded researchers:
Graham Dellaire, Departments of Pathology and Biochemistry & Molecular Biology
Characterization of HR-Killer1 and identification of small molecules for cancer therapy and enhanced gene editing using CRISPR/Cas9-based DNA repair strategies
Inherited diseases come from mutations in our genes, and genetic mutations are responsible for the development of a variety of cancers. These mutations arise from DNA damage that is repaired incorrectly in our cells. Researchers believe that if you can manipulate DNA repair, you can also enhance DNA damage in cancer cells as a therapy.
In 2013, it was discovered that DNA in human cells could be efficiently edited using a system from bacteria called CRISPR (Clustered Regularly-Interspaced Short Palindromic Repeats) that works with the cell’s DNA repair machinery. Through the creation of a new test for DNA repair based on CRISPR, Dr. Dellaire and his team have identified a small molecule inhibitor of DNA repair that they call HR-Killer1. With this new funding from CIHR, his team will test the ability of HR-Killer1 to selectively kill cancer cells, and will identify new compounds that enhance CRISPR-based gene editing for applications in gene therapy.
Susan Howlett, Department of Pharmacology
Impact of low testosterone on cardiac structure and function in aging
Heart disease increases with age in men and women as estrogen and testosterone levels fall. Since a women’s risk of heart diseases goes up after menopause, there has been a lot of interest in the idea the estrogen influences heart disease. However, it is now clear that testosterone decreases with age not only during “manopause” in men, but in women too.
Dr. Howlett and her team are looking at how long term exposure to low testosterone affects how the heart functions in males and females. Their findings from this project will provide a better understanding of the links between testosterone, aging and heart disease. It will also help determine whether testosterone supplementation is good or bad in vulnerable older people with heart diseases.
Matthew Herder, Health Law Institute and Department of Pharmacology
Beyond Transparency in Pharmaceutical Research and Regulation
Making pharmaceutical safety and effectiveness evidence transparent and accessible to physicians, researchers, healthcare payers and patients is an essential but elusive goal. Although a variety of new laws and policies have been put into place to increase transparency, meaningful improvements have been slow to arrive and changing the real world practices of regulators, clinical researchers and industry remains a huge challenge.
Professor Herder and his team will work with Health Canada and other key knowledge users to determine the following:
• How pharmaceutical data can be made more transparent to researchers;
• what procedural, social and political factors constrain Health Canada’s ability to enforce greater transparency; and,
• how the regulator can communicate and collaborate with clinical researchers, research institutions and funding agencies to improve pharmaceutical transparency.
Petra Kienesberger, Department of Biochemistry & Molecular Biology
Autotaxin-lysophosphatidic acid signaling in obesity-related heart disease
Obesity is a serious health problem in Canada. Insulin resistance and type 2 diabetes are the main complications of obesity that often damage heart muscle cells, leading to heart muscle weakening and possibly heart failure
Dr. Kienesberger and her team are studying what is happening in heart muscle cells of obese people with insulin resistance or diabetes that leads to heart muscle weakening. They specifically examine the role of bioactive fat molecules in this process, which are released by fat tissue, circulate in the blood stream, and are elevated during obesity and insulin resistance.
Research in the Kienesberger laboratory will help develop new and better ways to treat obesity and diabetes-induced heart muscle weakening, and lower the burden of obesity and diabetes on the Canadian health care system.
Angelo Iulianella, Department of Medical Neuroscience
Molecular regulation of neocortical circuit formation in a model for neurodevelopmental disorders
Neurodevelopmental disorders (NDDs), such as hydrocephaly, lissencephaly, autism spectrum disorder (ASD) and intellectual disability affect up to one in eight children born and represent a significant challenge to the health care system and resources available to Canadian families. NDDs are thought to arise from abnormal brain formation in the fetus, yet the underlying genetic and cellular mechanisms remain largely unknown and treatment options are extremely limited.
Dr. Iulianella and his team have identified a new regulator of neocortical organization that gives several hallmarks of development disorders of the human brain when mutated in mouse models. Their study will help advance our knowledge of the cellular and molecular processes that contribute to the formation of the neocortex and its connections to the regions of the brain important for emotion and cognition. They also hope to identify diagnostic events and therapeutic strategies for addressing developmental disorders of the brain.
Andrew Makrigiannis, Department of Microbiology and Immunology
Understanding Class I MHC Receptor Control of Natural Killer Cell Memory
Adaptive immune memory is one of the most powerful weapons the body has to fight infections. It is essentially how vaccines work: the immune system sees harmful, foreign matter and T and B cells remember it so that the immune response is stronger and faster the next time that target is encountered.
Surprisingly, natural killer cells, which are a cousin to the T cell, can also remember these targets, in a process that is not yet well understood. Dr. Makrigiannis’ research seeks to better understand what Ly49I, a specific natural killer cell protein, does that allows memory in these cells and identify which other proteins and helper cells contribute to natural killer memory.
A whole new field of study in immunology will be opened up by learning how this memory works, and it could also lead to novel cancer vaccines and therapies designed to prevent the recurrence of a dormant cancer.
Kirill Rosen, Department of Biochemistry & Molecular Biology
Molecular hallmarks of breast cancer sensitivity to ErbB2-targeted therapies
Many breast tumors are driven by a protein ErbB2, which they overproduce. These tumors are treated with drugs called ErbB2 inhibitors, but not everyone benefits from them. In addition, these drugs can damage the heart and are costly, so being able to determine who would and would not benefit from them is very important.
Breast tumor cells originate from normal breast cells forming a layer in the breast. Normal cells die when they detach from this layer. ErbB2 blocks the death of cancer cells after they detach, which allows them to form tumors and spread throughout the body. How ErbB2 causes these effects is not well understood.
Dr. Rosen and his team have discovered that ErbB2 triggers signals that cause a loss of a protein, known as Irf6, in tumor cells after they detach from their normal location, and that Irf6 reduces a cellular amount of a cell death-inducing protein known as Perp. Cells lacking Perp do not die outside their normal location.
In this research project, they will examine what signals ErbB2 induces to cause Irf6 and Perp loss in breast tumor cells, and whether this loss allows the cells to form tumors and spread through the body. Some ErbB2-overproducing tumors are treated with ErbB2 inhibitors in an effort to shrink the tumor, which is then surgically removed. The patient further receives these drugs to kill tumor cells that may have stayed in the body.
By testing human breast tumor samples obtained before and after treatment with the drugs, Dr. Rosen will be able to assess whether the increase in Irf6 and Perp levels in the tumor after it is forced to shrink by the drugs predicts whether the patient will benefit from these medicines. Patients that are not expected to benefit from the drugs would be able to avoid them after surgery. They are hoping to identify a new breast cancer mechanism and to develop a method of predicting who will benefit from ErbB2 inhibitors.
Xianping Dong, Department of Physiology and Biophysics
Functional crosstalk between TRPML3 and BK in autophagy induction and pathogen defense
Bacterial infections are the most common medical conditions. They often result in considerable economic and public health burdens and can have a large impact on the quality-of-life of the individuals affected. Although patients suffering from bacterial infections are commonly treated with antibiotics, these treatments can result in the development of antibiotic resistance. For this reason, alternative therapies are needed.
Dr. Dong and his team have discovered that there are two endolysosomal membrane ion channels, called BK and TRPML3, can increase pathogen clearance by increasing autophagy. They also predict that chemicals promoting TRPML3 and BK activity could be used to combat bacterial infection.
Kenneth Rockwood, Division of Geriatric Medicine
Determine how frailty influences the risk and expression of dementia in Alzheimer disease
Dementia is a clinical syndrome in which impaired memory and thinking interferes with a person’s daily life. The most common cause of dementia is mixed Alzheimer disease (AD) / vascular dementia. AD can be diagnosed clinically when someone is alive and, after death, by brain autopsy. Even so, not everyone who meets the autopsy diagnostic criteria for AD actually has dementia in life. Despite some study, why this discrepancy exists is still unclear.
Dr. Rockwood and his team plan to address it by looking at how overall health affects brain function. To do this, they will measure health problems, which they will quantify with a frailty index. The frailty index counts the number of health problems that an individual has accumulated. Frailty increases the risk for many age-related illnesses (including heart disease, hip fracture and dementia). They want to know if this helps explain why brain autopsy findings alone do not account for the clinical features of dementia.
Dr. Rockwood hypothesizes that the frailer a person is, even though it is more likely that they will have cognitive impairment, this will be less clearly related to their brain autopsy findings. They will use data from two large, community-based, autopsy series in older people (Chicago USA; Cambridge UK). The people in those studies generously agreed to have their memory and thinking tested every 1-2 years and to donate their brains after they had died.
This research team includes physicians who study both dementia in people and AD in brains, as well as scientists skilled in data analysis. They have team members at varying levels of their careers, from PhD student to established professor. Understanding how frailty affects brain function can improve our understanding of how dementia arises, and how it can be treated and even prevented.
John Sapp, Division of Cardiology
Comparing the effectiveness of medication versus cardiac ablation in the treatment of the dangerous arrhythmia, ventricular tachycardia.
The VANISH2 trial is designed to determine the best treatment for people who have life-threatening abnormalities of heart rhythm. Heart attacks leave scars in the heart muscle. The scars can interfere with the normal signaling within the heart that controls the heartbeat. In some cases, the interference can cause a very dangerous abnormal heart rhythm known as ventricular tachycardia (VT). This rhythm is the most common cause of sudden death in Canada.
When patients are at high risk for recurrences of VT, a defibrillator (ICD) can be implanted which can shock the heart back to normal rhythm from a cardiac arrest. These devices are life-saving but do not prevent the abnormal rhythm, they just provide a rescue when it occurs.
In order to prevent dangerous arrhythmias, doctors use strong rhythm control drugs or a procedure called catheter ablation. An ablation is performed by advancing wires through the blood vessels into the heart, using X-rays and other imaging to see where they are and the short circuits within the scar can then be identified and interrupted (ablated). Neither the drugs nor the ablation procedure work perfectly and both carry risk. This trial is designed to determine which treatment is the best.
Patients who have had heart attacks and develop VT will be randomly allocated (50:50) to be treated either with rhythm control drugs or catheter ablation. All patients will receive an implanted defibrillator. We will enroll a total of 366 patients and follow them for at least two years to see which group does the best with respect to recurrent abnormal heart rhythms and survival.
This trial will determine whether the best treatment for VT is heart rhythm drugs or catheter ablation. This evidence will permit more optimal treatment for many thousands of patients worldwide.
Phil Tibbo, Department of Psychiatry
Investigating cannabis effects on brain structure and disease course in early phase psychosis.
Schizophrenia, affecting 1{8617e24ab0b76aabcd10cf8004a7bdc562123dc1ea8adc37299158a7c05423e6} of the population, causes significant burden to individuals, families and society. Fortunately, specialized early phase psychosis (EPP) intervention programs result in positive long term outcomes.
Unfortunately, the high rate of cannabis use in EPP affects these outcomes. Cannabis use results in a higher risk of relapse and severity of symptoms, reductions in individuals following thru with treatment and overall functioning deficits (e.g. work and school) compared to EPP non-cannabis users. Cannabis use can reduce the recovery gains of these young adults. Cannabis, thru its receptors located on the brains white matter (WM) tracts, may be affecting WM development during the critical brain developmental period of young adulthood, resulting in these negative outcomes. Damage to the connections in the brain have themselves been reported in long-term schizophrenia, potentially causing schizophrenia symptoms.
The effects of regular cannabis use, on a potentially already damaged brain in early disease, has not been well studied but we suspect that it too reduces the strength of brain connections but in a different way than schizophrenia.
Dr. Tibbo’s two site study (Halifax, NS; London, Ont), will recruit subjects to four groups: cannabis use disorder (CUD) and non-CUD patients within the first year of entry to the EPP programs, and CUD and non-CUD age and sex matched healthy controls. They will collect detailed information about past and current use of cannabis and clinical measures using established rating scales and methods. They will combine novel brain imaging techniques focusing on WM to generate an understanding of specific WM abnormalities associated with cannabis use in EPP, separate from illness and cannabis effects alone.
This research design will allow a pioneer assessment of the potential negative impact of regular cannabis use longitudinally in this population (baseline and one year later), allowing for more directed education and treatments.
For more information about CIHR’s project grants, visit the CIHR website.
