Elucidating the Impact of In Utero GDM Exposure on Offspring Circadian Insulin Secretion

$49,986 awarded to Drs. Christine Doucette & Peter Thompson.

Gestational Diabetes Mellitus (GDM) is the development of high blood sugar during pregnancy that resolves once the baby is born. Having GDM creates short and long-term health risks for both the mom and baby. New evidence shows that babies born during a GDM pregnancy have a greater chance of developing type 2 diabetes, particularly during childhood. Using an animal model, our prior work discovered that if a baby is born to a mom with GDM, but lives a healthy lifestyle after birth, they still develop problems with making insulin, the hormone that regulates blood sugar. We also found that GDM-exposed babies do not develop “normal” circadian rhythms (i.e. daily rhythms of various biological processes). Circadian rhythms of insulin production are essential for blood sugar control such that higher insulin production is needed during the day when we expect food intake and lower at night when we are sleeping and not eating. We know little about how these daily cycles of insulin production are controlled and how GDM exposure in the womb affects circadian cycles of insulin in the child. We predict that the insulin-making cells of the body require a daily “rest and repair period” at night to ensure proper energy to support insulin production during the day. Our idea is that the “rest and repair period” is insufficient in GDM-exposed babies, causing them to accumulate damage, making them less capable of producing insulin and more likely to develop diabetes. Here, we will use insulin-making cells to understand how daily cycles of rest and repair influence insulin production.  Additionally, we will use our GDM mouse model to explore how GDM exposure influences the “rest and repair” cycles in babies. Why do we need to do this? Alarmingly, children who have type 2 diabetes tend to develop diabetes-related complications much more rapidly and aggressively than adults with type 2 diabetes, including lower limb amputations, blindness, and kidney failure. Since GDM exposure greatly increases the risk for childhood type 2 diabetes in the baby, we urgently need to understand how GDM makes a child more susceptible to diabetes so that we can appropriately intervene in early life to prevent the development of type 2 diabetes and its devastating complications.

Vascularized 3D Lung Models to Examine Concurrent Resolution of Airway Inflammation and Infection

$50,000 awarded to Dr. Neeloffer Mookherjee.

Asthma affects more than 4.5 million Canadians, which is approximately 60% higher in children compared to adults making it the most common chronic disease in children. Asthma causes lung inflammation and narrowing of the airways, making it difficult to breathe. In children with asthma, infections with a common cold virus known as human rhino virus (HRV) can worsen the disease and make it difficult to treat with available therapies. This results in severe disease and is the most common cause of hospitalization for children. Thus, there is an urgent need for new treatments that can reduce lung inflammation while also controlling HRV infections.

This study focuses on new molecules known as Innate Defence Regulator (IDR) peptides. These peptides can fight infections and can also control lung inflammation. Our previous research has shown that IDR peptides improve breathing capacity and controls cellular processes linked to severe asthma. Therefore, this study will examine the ability of IDR peptides to simultaneously reduce lung inflammation and HRV infections. To achieve this goal, we will use the world’s first human Lung-on-Chip models to investigate the impact of HRV infection under inflammatory conditions. Secondly, we will test IDR peptides for its ability to resolve both inflammation and infections.

This is an unique international collaborative study; Dr. Anne van der Does (Collaborator) leads the only research group in the world to have developed working Lung-on-Chip models, while Dr. Mookherjee is a world leader in the study of IDR peptides for asthma. This international collaboration will be the first study with potential to directly advance the development of new ‘dual function’ therapies that can control inflammation and help resolve HRV infections in severe uncontrolled asthma, for which there are no treatments.

Restoring Mitochondrial Oxidative Metabolism for the Treatment of Diabetes

$50,000 awarded to Dr. Vernon Dolinsky.

Gestational diabetes (GDM) is a type of diabetes that can happen during pregnancy. It means the mother’s body does not use insulin properly, so her blood sugar gets too high. This condition is becoming more common. GDM can lead to babies being born heavier and it can also cause the mother and baby to have a higher risk of becoming overweight or having diabetes later in life. Scientists are not exactly sure what causes GDM, but one part of the body that plays a big role is the liver. The liver helps provide sugar (glucose) to both the mom and the baby. If the liver has too much fat in it, it can’t control how much sugar it produces, and this can lead to diabetes. Within our cells, mitochondria act like engines, helping the body turn food—especially fat—into energy. Our lab found that in pregnant mice with GDM, the mitochondria in the liver don’t work properly and cannot break down fat. This causes fat to build up in the liver and makes blood sugar rise. We are studying a protein called SIRT3 that controls how mitochondria work. In mice with GDM, SIRT3 levels are lower than normal. Our project will test three ways to boost SIRT3: a nutritional supplement, gene therapy, and a new method using tiny fat-based particles called lipid nanoparticles. We want to see if boosting SIRT3 can help the mitochondria work better, lower liver fat, and treat diabetes during pregnancy. This better treatment for GDM could help make both mothers and their babies healthier and lower the risk of type 2 diabetes in children.

Examine the Role of Growth Differentiation Factor 15 in Regulating Placental Hormone Synthesis

$50,000 awarded to Dr. Lei Xing.

The human placenta is a crucial organ that supports the health of both the mother and the fetus during pregnancy. It helps deliver oxygen and nutrients to the fetus while removing waste products. Hormones and signalling molecules control most of the placenta’s functions by entering the mother’s and fetus’s bloodstream. But scientists still don’t fully understand all the molecules that the placenta releases during pregnancy or how they help maintain pregnancy and support fetal growth. Since the placenta can vary greatly across different species, animal models like rodents don’t always reflect human placental biology well. To solve this, better and more accurate models are needed to study the human placenta.

This research will use human stem cells to grow trophoblast organoids—3D mini organs in a dish that mimic the human placenta. These organoids will help us better understand which molecules the placenta releases at different stages of pregnancy and how they affect the health of the placenta, mother, and fetus. We believe that these organoids can closely model the structure and function of the human placenta to study its role in pregnancy. The study will also focus on a specific molecule secreted by the placenta called growth differentiation factor 15 (GDF15), which has been linked to pregnancy complications and fetal brain development. Using gene editing tools, we will make GDF15 knockout organoids and compare them to normal ones. This will help us understand how GDF15 influences pregnancy hormones and placental function, and how these changes, in turn, affect fetal growth.

Our work will offer a new model to study the human placenta, offering insights into pregnancyrelated complications. It may help reveal the causes of pregnancy problems and suggest ways to
prevent them. In the long run, this could lead to better and more effective treatments for pregnancy-related or developmental issues, leading to better outcomes for mothers and babies.

Identifying the Role of Protein Aggregates in Beta-cell Failure During Pregnancy: A New Insight into Pathogenesis of Gestational Diabetes

$49,800 awarded to Dr. Lucy Marzban.

Diabetes in pregnancy is caused by failure of insulin producing cells to release enough insulin for the body’s higher needs during pregnancy. This results in increased blood sugar during pregnancy. High blood sugar in pregnancy is one of the most common conditions in pregnancy. It can lead to serious problems for both the mother and the baby during pregnancy. It also increases the risk of diabetes later in life in the mother and the child. The factors that damage insulin producing cells during pregnancy and increase the risk of diabetes after pregnancy are not clear.

We propose that the changes which happen in the mother during pregnancy, to support the baby’s growth, can initiate the formation of harmful proteins in some of the mothers and their babies. These harmful proteins can damage insulin producing cells, leading to high blood sugar during pregnancy. This damage is not reversible and continues after pregnancy, so it can also increase the risk of high blood sugar later in life.

We have developed a mouse model that forms these harmful proteins, like those formed in humans. We will use this model to assess the formation of harmful proteins during pregnancy and their role in causing high blood sugar in pregnancy. We will also follow these mice after pregnancy and their pups after birth to find out if harmful proteins can increase the blood sugar later in life in the mother and offspring. Finally, we will validate a blood test for early screening of individuals at risk for high blood sugar in pregnancy. We have developed novel research techniques that help us do these studies.

Through this project, we hope to find one of the key factors that cause increased blood sugar during pregnancy. We also hope to develop a test for early detection of people at high risk for diabetes in pregnancy. These studies are key steps towards finding ways to prevent high blood sugar during pregnancy and later in life in the mother and offspring.

Ataxia Pathogenesis: Role of the Frataxin Gene in Impairments of the Cerebellar Nuclei

$50,000 awarded to Dr. Hassan Marzban.

Understanding How Cerebellar Dysfunction Contributes to Friedreich’s Ataxia

Friedreich’s ataxia (FA) is a rare inherited brain disorder that usually begins in late childhood or early adolescence. Children with FA often develop worsening problems with coordination, balance, and movement. The condition can also lead to heart disease and a higher risk of diabetes. FA is caused by a change in a gene that reduces the production of a protein needed for healthy cells. This research focuses on the cerebellum, the part of the brain that controls smooth and coordinated movement. In FA, the cerebellum is one of the most affected areas, but it is still unclear how problems in this brain region contribute to the symptoms and how the disease worsens over time. Our study will look at how the loss of this important protein in certain brain cells affects how the cerebellum works. To do this, we will use a technique to switch off the gene in the cerebellum of specially bred mice and study specific types of brain cells. We will then test the mice’s movement and examine their brain tissue to see the changes at the cellular level. By understanding how early damage in certain cerebellar cells leads to FA, this project may uncover key causes of the disease. Our findings could lead to earlier diagnosis and better treatment options for children and youth living with FA. Although FA is rare, it affects approximately 1 in 40,000 people, including families in Manitoba.

Validating Case Definitions of Youth Mood and Anxiety Disorders in Administrative Data

$50,000 awarded to Dr. Amani Hamad.

Depression and anxiety are the most common mental health problems in youth (ages 13-18 years). In Canada, about one in ten youth are affected. These conditions are becoming more common and can have long-term effects.

To support youth mental health, we need to understand what puts them at risk. We also want to know how these conditions affect them over time and if treatments work well. To do this, researchers often use healthcare use records. These include records of hospital and doctor visits, and prescriptions. But right now, there is no reliable way to find out which youth have depression or anxiety in these records. This makes it hard to conduct strong research or plan the right programs.

Our study will test different ways to find youth with depression or anxiety in healthcare use records. First, we will review medical charts from pediatric, psychiatry and family doctor clinics to find out who has these conditions. Then, we will link these clinic records to Manitoba’s healthcare use records. We will compare different methods to see which one correctly finds youth with these conditions. We will check if these methods work equally well for boys and girls, youth in rural and urban areas and youth from different income levels. We will also test whether they still work well over time.

This study will help us find the best way to find youth with depression or anxiety in healthcare use records. This will improve future research and guide better mental health programs.

Predicting the Effects of Weight Loss Drugs on Childhood Obesity Growth Trajectories and Health Care Costs in Canada

$50,000 awarded to Dr. Shweta Mital.

In Canada, over 1.5 million children are overweight or obese. This puts them at risk for chronic diseases in adulthood. The Canadian Clinical Practice Guidelines for managing pediatric obesity were recently updated in response to this crisis. New weight loss drugs are also entering the Canadian market. As evidence about their benefits grows, and debates on Universal Pharmacare continue, there is increasing pressure on payers to cover these drugs.

To make evidence-informed decisions, it is important to understand the size of the childhood obesity problem in Canada. We also need to know how it might change in the future. It is also important to determine whether treating adolescents with weight loss drugs could help reduce the crisis. Some past studies have looked at how children’s BMI changes over time. But these do not reflect the current Canadian children and teens. Further, no studies have looked at how new weight loss drugs could change future obesity trends in Canada.

This study will use advanced forecasting techniques and data from a world-leading study of Canadian children. It will examine obesity patterns and will predict future obesity rates. It will also assess how new weight loss drugs for children might reduce obesity in the future.

The Healthcare Preferences and Valued Outcomes of People Living with Congenital Heart Disease and their Care Partners: A Participatory Scoping Review (TRAILS-CHD-ScR)

$50,000 awarded to Dr. Anna M. Chudyk.

Congenital heart disease (CHD) is the most common birth defect in Canada, affecting about 4,400 babies every year. Thanks to medical advances, most people with CHD now live well into adulthood. However, they continue to face more health challenges and lower quality of life than people without CHD. One of the biggest hurdles happens between the ages of 16 and 25, when young people with CHD (YCHD) must move from pediatric to adult heart care. During this time, they need to build relationships with new healthcare providers and take on more responsibility for managing their health. Without the right support, up to 61% of young people with CHD stop receiving regular care, which puts them at greater risk for serious health problems.

This project aims to create a patient-centred transition program to support YCHD through this critical time. We will work together with YCHD, their family and friends (care partners), health and social care providers, and decision-makers to co-design this program. Our research will take place at Manitoba’s two main heart care centres: St. Boniface Hospital and the Health Sciences Centre. Using a proven step-by-step process called Intervention Mapping, we will combine research evidence with real-world experiences to understand the challenges YCHD face and the best ways to support them. We will use methods such as literature reviews, focus groups, and group discussions to gather ideas and make decisions together.

By the end of this project, we expect to have a first version of a new, patient-designed transition care program. We also hope to strengthen collaboration between YCHD, their families, and health and social care providers and decision-makers, and to create resources that help them work together to make better care decisions. In the future, this work will lay the groundwork for testing the program in hospitals and eventually making it available to CHD patients across Canada.

Physician and Caregiver Perspectives on the use of Medical Cannabis in Children with Autism Spectrum Disorder

$50,000 awarded to Dr. Lauren Kelly.

Manitoba Team: Lauren Kelly, Holly Mansell, Geert ‘tJong, M. Florencia Ricci, Sara Klassen, Wanting Ding, Jessica Overby

National Collaborators: Tim Oberlander, Hal Siden, Enav Zusman, Jennifer Anderson, Taylor Lougheed, Naomi Goloff, Blake Pearson

In Canada, it has been reported that between 1 in 50 and 1 in 25 children are diagnosed with Autism. Autism affects how people interact with others, connect, learn and experience the world in different ways and no two people with autism are alike. Children with Autism may have trouble communicating, adapting to changing environments, have strong interest in certain topics and show repetitive behaviors. Some medicines and other therapies can help families experiencing challenges, but they don’t always work and can cause side effects. Parents and families report accessing medical cannabis to help their child. Studies have showed that medical cannabis can improve outcomes in conditions like epilepsy, but we have little information about if medical cannabis works or is safe in children with autism.

Our goal is to learn more about the use of medical cannabis in children with Autism in Canada. We will ask parents and doctors about their opinions, concerns, and views on the positives and negatives (risks and benefits) of medical cannabis using surveys and interviews. We will survey more than 100 doctors who care for children with Autism and 50 parents of children using medical cannabis for Autism. After our surveys, we will interview about 10 doctors and 10 parents to learn more in depth about their experiences.

Our team is lead in Manitoba and includes pediatricians, parents, researchers and doctors who authorize medical cannabis for children with Autism from BC, Ontario and Quebec. This study will help us to learn more about medical cannabis for children with autism. The results from our work will be interpreted with the help of children with Autism and their parents to help us create educational materials and plan future research.