Genetics of healthy cardiovascular aging

Statistics Canada projects that there will be more than 1.6 million seniors over 85 by the year 2041. Only a minority who reach this age maintain a good quality of life and are free of major age-related diseases such as cardiovascular disease (CVD), cancer, lung disease, diabetes, and Alzheimer’s disease. Advancing age is the biggest risk factor for cardiovascular disease. However, a minority of people older than 85 — called “”super seniors”” — seem resistant to the most common age-related diseases, including CVD. These people may represent a group that either lacks genetic susceptibility factors that contribute to disease in the majority of people or may possess genetic resistance factors that enhance their ability to resist disease and prolong lifespan. Dr. Maziar Rahmani seeks to answer whether people whose hearts remain healthy well into their 80s and 90s have “good genes.” He is studying more than one thousand residents in the Metro Vancouver area, using cutting-edge technologies to scan the entire genome of each study participant. He will look across more than a million potential variances to find genetic commonalities among super seniors in Vancouver, and compare these findings to other studies using European and other North American populations. Identifying and understanding genetic factors that influence resistance or susceptibility to heart problems could open the way for personalized, optimized disease prevention and treatment strategies.

The role of SHIP in the development and function of myeloid immune suppressor cells

An important role of the immune system is to identify and eliminate tumour cells. When a tumour first forms, the immune system recognizes it as foreign and generates specialized T cells to attack and kill it. However, tumours have evolved a number of mechanisms that prevent the immune system from being able to function properly, resulting in cancer progression. One of the mechanisms by which tumours escape from the immune system is by secreting chemicals that promote the generation of cells that inhibit T cells from carrying out their normal functions. The presence of these suppressive cells is one of the most common reasons current cancer therapies fail. Melisa Hamilton is investigating a specific subset of these suppressive cells, called myeloid immune suppressor cells (MISCs). Previous research has shown that the protein known as SHIP is important in regulating the survival and proliferation of myeloid cells (white blood cells). Hamilton’s research is focused on investigating the specific role SHIP plays in MISC development and function. With a better understanding of how tumours stimulate the development of MISCs and how these cells suppress the immune system, researchers can design targeted therapies to prevent the formation and function of MISCs. These therapies would greatly increase the ability of the immune system to attack and eradicate tumours and would be especially effective in combination with current cancer immunotherapy treatments to improve cancer patient outcomes.

Endogenous cell replacement: progenitor characterization and promotion of oligodendrocyte differentiation and remyelination in the central nervous system by attenuating myelin inhibition

White matter is the part of the nervous system composed mainly of nerve fibres covered by a lipid-dense sheath of myelin. Myelin is produced by cells known as oligodendrocytes, and is responsible for increasing the speed of electrical impulses throughout the nervous system. White matter disorders, such as multiple sclerosis (MS) and spinal cord injury (SCI), comprise a devastating group of conditions that affect millions of people around the world. Although these disorders may have different features, they are all characterized by myelin damage that will not sufficiently repair (remyelinate). While the exact cause of this insufficient remyelination is unknown, one thing is clear: for myelin repair to occur, oligodendrocyte precursor cells (OPCs) need to proliferate and migrate to areas of demyelination, to differentiate, and to then remyelinate denuded neurons. While the transplantation of cells with the potential to myelinate is feasible, there are significant barriers for effectively translating this technology into clinical treatment. An alternative strategy is to activate precursor cells within the host tissue (endogenous cells) to mobilize and promote repair. Jason Plemel was previously funded by MSFHR for his work studying oligodendrocyte transplantation following spinal cord injury. He is now exploring the dynamics of cell-based repair via endogenous cells. He is studying the capacity of oligodendrocytes to self-renew and replicate under normal and disease conditions. He is also investigating possible inhibitory signals at the region of damage that could inhibit endogenous repair, and whether these signals could be blocked to promote remyelination. Plemel anticipates that this work could ultimately lead to new targets for drugs that promote regeneration of myelin in a number of white matter disorders.

Prediction of cardiovascular mortality in patients with coronary artery disease using plasma and genetic markers of oxidative stress

Coronary artery disease (CAD) is the leading cause of death worldwide. The consequences of CAD severely burden the Canadian health care system, and expensive therapeutic solutions have only limited capacity for preventing or reversing the disease. Oxidized low density lipoprotein particles (oxLDL) contribute to the progression of CAD. OxLDL are a harmful byproduct produced by oxidative stress, which occurs when the production of free radicals in the body exceeds the body’s ability to neutralize and eliminate them. The environmental factors that increase the risk of CAD, such as poor nutrition, smoking, obesity, and low physical activity, are the same factors that increase oxidative stress levels in the body. Claire Heslop is studying the influence of oxidative stress on long-term survival among people with CAD, and investigating genetic differences that contribute to this relationship. She is evaluating whether markers of oxidative stress in the blood, as well as markers of inflammation, can predict risk of death from cardiovascular disease in individuals with CAD. She will also investigate oxidative stress genes to determine how inherited differences affect oxidative stress in the blood, the risk of CAD, and the risk of cardiovascular death. As part of this project, the relationships between CAD, oxidative stress markers and various physiological, lifestyle and socioeconomic risk factors will also be examined. Heslop’s work will contribute to our understanding of the role oxidative stress plays in coronary artery disease. This study may inspire the creation of new tools for diagnosing CAD and predicting long-term risk.

Early mother-infant interaction and infant mental health

The quality of the mother-infant relationship early in infancy forms a foundation for infants’ subsequent social and emotional development. In particular, mothers’ sensitive responses to behavioural and emotional cues help their infants develop a sense of self and help them regulate their emotions. Attachment — or the bond between infants and their caregivers — is a developmental achievement in the first year of life that is essential for healthy physical and psychological growth. Studies have shown that insecurely-attached infants are at risk for a range of negative developmental outcomes. Nancy Mcquaid was funded by MSFHR for her early PhD work into the relationship between attachment and infant mental health. She is continuing this longitudinal investigation among a community sample of mothers and their infants. Mcquaid’s research is now evaluating whether maternal responsiveness and infant social expectations observed at four months are related to subsequent infant mental health at 12 and 30 months of age. She is also assessing the impact of mother and infant temperament to healthy developmental outcomes. Mcquaid’s research will contribute to our understanding of healthy infant development and will help develop means of intervention for infants who are at risk for developmental emotional and interactive disturbances, such as infants of mothers with postpartum depression and low birth weight infants.

Production of high-quality proteins in plants for screening and treatment of human lysosomal storage diseases

Lysosomes are structures that digest materials within the cell. Lysosomal storage diseases are devastating diseases caused by deficiencies of specific enzymes within the lysosomes. Mucopolysaccharidosis I (MPS I) is a progressive lysosomal storage disease that affects most organ systems. In severely affected humans, this genetic disease leads to early death because of profound disturbances to the heart, brain and other organ systems. One way to correct lysosomal enzyme deficiency is through using purified enzymes for enzyme replacement therapies (ERT). However, the current methods used to commercially produce the enzymes for ERT are prohibitively costly. Because of this, sustained financial support for ERT among affected Canadians is uncertain. Dr. Allison Kermode is exploring whether using plants as hosts to produce these human enzymes will offer a more economical way to provide ERT treatments for MPS I, as well as for Gaucher disease, another lysosomal storage disease. She will test whether plant-made human enzymes are effective as ERTs. She will also establish a plant-based system for assessing potential small molecule treatments for these diseases. Finally, in collaborative work, Kermode will test plant-made lysosomal enzymes in assays for newborn screening of lysosomal storage diseases. Some of the research will be expanded to other therapeutic proteins relevant to Type I diabetes, providing a general platform for plant production of therapeutic proteins.

Building the Evidence-base to Support Rural Maternity Health Services Policy and Planning

Dr. Stefan Grzybowski is a family physician clinical investigator and co director of the Centre for Rural Health Research within the Vancouver Coastal health Research institute. He is co-Principal Investigator of the Rural Maternity New Emerging Team, funded by the Canadian Institutes of Health Research and also co directs the British Columbia Rural and Remote Health Research Network, a Health of Population Network funded by the Michael Smith foundation. Prior to moving to Vancouver in 1994, Dr. Grzybowski practiced for 12 years as a family physician on the Queen Charlotte Islands/Haida Gwaii.

Dr. Grzybowski’s research has focused on building an evidence base supporting sustainable maternity health services for rural parturient women, translating this evidence into policy and practice and building research capacity for primary care clinician researchers. His interest in rural health services research was fostered by his experiences in facing the challenges of providing limited maternity services in an isolated hospital on the Queen Charlotte Islands without local access to Cesarean Section. His current projects include developing a Logic Model for sustainable rural maternity care in three isolated BC communities, investigating mechanisms in which GP surgery can be supported in BC, measuring population based maternal and newborn outcomes for rural service catchment areas across BC, and measuring stress associated with pregnancy for parturient women living in rural communities.

Pharmacy Immunization Community Strategy

Influenza is a major cause of morbidity and mortality in Canada. Community attack rates range from 10 to 20 percent, but can be more than 50 percent in closed settings such as residential care facilities or schools. In BC, influenza vaccine is provided free to hose at increased risk of severe disease and/or death from influenza infection, including the elderly and people with chronic health conditions. Despite access to free vaccine, adult immunization rates in the eligible population remain too low.

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Expiratory flow limitation, dynamic hyperinflation and respiratory muscle fatigue during exercise in men and women

The act of breathing is a complex physiological process involving the interaction of numerous respiratory muscles and a neural control network. These respiratory muscles are the only skeletal muscles in the body whose functioning is necessary to sustain human life, making their ability to resist fatigue very important. Despite this, research has shown that high intensity exercise can induce respiratory muscle fatigue. Given the life-sustaining role of the respiratory muscles, it is important to understand the mechanisms of fatigue, how it is best detected, and how the human body responds and adapts to fatigue. Also, research suggests that physiological and anatomical differences may make women more susceptible to respiratory muscle fatigue compared to men. However, there are no studies that have systematically examined sex-based differences in respiratory muscle fatigue, and the “normal” pulmonary response to exercise in women is not well understood. Jordan Guenette was previously funded by MSFHR for his early PhD work identifying the respiratory limitations women face as they age. Now, he is examining the mechanisms and consequences of respiratory muscle fatigue in men and women during whole body exercise. His study will determine if the smaller lungs and airways in women cause greater respiratory muscle fatigue compared to men. He will also investigate whether high levels of respiratory muscle work reduce blood flow to other parts of the body and are responsible for impairment of whole body exercise performance. Guenette’s project will address questions significant to both basic and clinical science, outlining how men and women differ with respect to the normal pulmonary physiology of exercise. His findings have the potential to influence exercise rehabilitation programs for a variety of patient populations, and exercise prescription to prevent disease in healthy individuals.

The role of secreted protein acidic rich in cysteines (SPARC) in neurogenesis and gliogenesis in the embryonic and adult mouse brain: applications to models of Cerebral Ischemia Reperfusion Injury

Stroke is the primary cause of adult disability in Canada. Recovering brain function after stroke is dependent on the brain’s ability to rewire itself and replace tissue that has died during the stroke – something that is difficult to achieve in the adult brain. Rewiring the brain requires that existing neurons sprout new fibres (axons) and connect to other neurons in a way that allows proper functioning of neural circuitry. Recovery also involves the birth of new cells to replace dead cells and to form functioning connections with new and existing neurons. These processes all occur within the extracellular matrix (ECM) – a network of fibrous proteins, gel-like sugars and linking molecules – and are promoted by a large number of growth factors and intercellular signalling molecules. Anthony Berndt’s research focuses on the role of the SPARC protein in the generation of new neurons. SPARC binds to the ECM and regulates the potency of growth factors that normally promote cell division and migration. Berndt is examining the influence of SPARC on the development of the embryonic brain and on the generation of new neurons in the adult brain. His studies will determine if SPARC’s presence or absence affects the rate or manner in which brain tissue regenerates after stroke. He hopes to formulate an approach that will prompt neural stem cells normally found in the adult brain to follow the developmental steps required to form functional tissue after stroke. By understanding the function of SPARC after brain injury, he could also determine at what point of recovery such an intervention would be of greatest use. By understanding the role of SPARC, Berndt’s research could eventually lead to improved therapies for treating major brain injuries by augmenting the body’s natural repair processes.