Associate Professor, Department of Pediatrics and Child Health
As the co-lead for the Research Manitoba-funded DEVOTION cluster, we will rely on the NGS platform to accomplish the following goals:
Scope of the Problem: Chronic non-communicable diseases (e.g. diabetes, chronic lung and cardiovascular diseases) are the leading causes of death, disability and health care expenditures worldwide7. When considered in relation to mortality and disability adjusted life years, the burden of chronic noncommunicable diseases eclipses that of infectious diseases8. Alarmingly, rates of chronic diseases are rapidly increasing among youth and young adults with substantial effects on the quality of life, productivity and lifelong healthcare costs9-12. It is possible that this rapid increase is related to population-changes in early life exposures (i.e. maternal gestational obesity/diabetes or exposure to chemicals) that contribute to the increase disease burden. In Manitoba, the prevalence and incidence of chronic diseases like asthma and diabetes among youth far exceeds that of other provinces in Canada13-16.
Mechanisms for early life programming of chronic disease risk in youth. While epidemiological studies clearly confirm that chronic diseases in adulthood have their origins in early life, the biological mechanisms by which fetal and early life exposures influence physiology and health of children and youth are complex and remain unclear17-20. Two traditionally proposed mechanisms involve (1) permanent structural changes to key organs (i.e destruction of fetal pancreatic beta cells increasing diabetes risk and lung dysplasia following mechanical ventilation increasing risk for chronic lung disease) and (2) accelerated cellular ageing (i.e. oxidative stress-induced shortening of telomeres leading to cellular senescence and premature age-related pathologies; reviewed in18). More recently, epigenetic regulation of gene expression17-20 and perturbation of the commensal microbiota21-23 have been identified as novel mechanisms that link early life events to chronic disease risk. We will capitalize on existing infrastructure to rapidly expand our understanding of how early life factors program risk for chronic diseases in youth early in life through epigenetic modifications in risk alleles.
Epigenetics: The epigenome is a complex layer of regulatory information superimposed on the genome and includes nucleosome occupancy, positioning, composition, modification and dynamics, as well as DNA methylation that influence the expression of genes24-26. Due to phenotypic plasticity in early life, epigenetic mechanisms are very significant in the maternal-placenta-fetal transmission of disease phenotypes27. Epigenetic modification of DNA contributes to the transmission of risk from mother to child during gestation and contributes to the offspring’s susceptibility to chronic diseases28-31. Moreover, epigenetic programming can be influenced by how the offspring are nursed, by infection or allergen exposure or even by how the gut is colonized by bacteria32. Epigenetic programming of gene expression may also have an intergenerational effect and as a result may perpetuate chronic disease in the next generation33. Enhancing our epigenomic research capacity will increase our understanding of how the timing and type of early life environmental exposures (e.g. gestational diabetes, maternal diet, stress, allergens, etc.) contribute to chronic disease susceptibility (obesity, asthma, diabetes). Our research will identify epigenetic signatures that could serve as novel biomarkers of disease risk early in life and identify pathways that may be targeted for proof of principle interventional studies to prevent chronic disease in youth.
Specific Studies: Members of the DEVOTION cluster (n=26) will study the role of epigenetic modification of genes involved in the natural history of a range of chronic diseases including but not limited to: (1) type 2 diabetes in youth, (2) diabetes-related cardiac and renal disease in youth, (3) congenital diaphragmatic hernia; (4) obesity and (5) asthma and allergy. Finally we will examine the effects of various early life interventions on rescuing or reversing adverse epigenetic signatures in high risk youth.
511 John Buhler Research Center