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CIHR Fall Project Grant Success

Two CHEO RI researchers have been awarded Project Grants from CIHR with two others as co-Principal investigator. The projects are in the areas of bronchopulmonary dysplasia, congenital myasthenic syndromes, the prevention of Group B Streptococcal and milk microRNAs and will allow researchers to move discoveries forward significantly in improving newborn, child and adult health. Congratulations to Senior Scientists Dr. Robert Jankov and Dr. Hanns Lochmüller, Scientist Dr. Deshayne Fell and Investigator Dr. Emanuela Ferretti. Dr. Jankov and Dr. Lochmüller both ranked second in their panels. The CHEO RI had a 17% success rate; the overall CIHR approval rate was 15%.

The projects, in order of amount funded, are:

Dr. Hanns Lochmüller received $1,025,100 over four years for Inherited disorders of neuromuscular transmission in humans: understanding and manipulating molecular and cellular structure-function relationships at the motoneuron to muscle interface, the neuromuscular synapse, through a translational medicine approach.
Voluntary movement of muscles in humans requires electric signalling from the nerve cells in the spinal cord to the muscles that help us speak, eat, breathe and walk. This process, called neuromuscular transmission, can be impaired by poisoning, autoimmunity, ageing, and genetic disease. In this research project, Dr. Lochmüller proposes to study gene mutations that lead to impaired neuromuscular transmission, so-called congenital myasthenic syndromes (CMS). CMS usually start at birth or early childhood, cause severe muscle weakness, and are often fatal because of respiratory complications. Effective drugs are available to treat CMS, but to select the best drug we need to understand the underlying genetic mutation and its effect on neuromuscular transmission. We currently know about 35 different genes that can cause CMS, many of which were discovered by Dr. Lochmüller’s research team. However, around 40% of all patients with CMS do not have a genetic diagnosis and available drug therapy is not effective for 50% of patients. The goal of the project is to improve the diagnosis and treatment of CMS. Specifically the project will: 1. Provide a genetic diagnosis for patients with CMS and discover new CMS genes. Researchers will use genomic sequencing (decoding a person's DNA) to identify gene mutations that cause CMS in a group of 1000 patients with CMS. 2. Understand how gene mutations cause CMS to identify the most appropriate drug or new targets for drugs. The team will study the underlying defects in cell and animal models using a variety of scientific techniques. 3. Develop new drug therapies for CMS by testing them in cell and animal models. Researchers will test a variety of drugs in cell and animal models. This research will lead to better diagnosis and therapies for Canadians affected by CMS. Knowledge gained through this research will improve the understanding of neuromuscular transmission disorders.

Dr. Robert Jankov received $726,750 over five years for Elucidating a role for Rho-kinase-thrombospondin signaling in experimental and human bronchopulmonary dysplasia: Novel targets for prevention and treatment of chronic lung disease in premature newborns.
About 1,500 babies are born extremely premature in Canada each year. Advances in medical care over the last 20 years have improved the survival of these babies, but in about half at the cost of a severe injury to the lung called bronchopulmonary dysplasia (BPD). Babies with BPD suffer from a permanent interruption of normal lung development; therefore, they carry their lung disease with them their entire lives and in the most severe cases die before school age. Medical costs related to BPD are among the highest for all childhood diseases, being second only to asthma. Preventing disease due to prematurity is therefore of critical importance to the health of Canadians. The proposed experiments will use animals with experimental BPD and lung tissues from human newborn infants to define and confirm the involvement of specific pathways leading to lung injury: Rho-kinase (ROCK) and thrombospondin (TSP)-1. Researchers will give a promising class of drug by inhalation, known as a ROCK inhibitor, to determine safety and efficacy in rats with BPD. Another molecule regulated by ROCK is TSP-1, which the team’s work suggests is critical to interruption of normal lung development. Importantly, researchers will allow rats to grow into adults to see whether benefits of targeting ROCK and TSP-1 are long-lasting. Researchers who are part of this project are uniquely equipped with the facilities and expertise to perform the experiments that are proposed. In particular, this group is the only group possessing the ability to perform precise measurements of lung structure using a technique called "unbiased stereology". Collectively, these experiments represent a critical step toward the translation of novel drugs targeting molecules implicated in BPD, which could represent a breakthrough in the ability to improve health outcomes among Canadians who were born premature.

Dr. Emanuela Ferretti is co-Principal Investigator on the Effect of human milk exosomal microRNAs on intestinal cells, a $661,726 project funded over three years.
Human milk promotes intestinal growth, immune modulation and a healthy microbial environment. These benefits are particularly important for premature infants. Deficiencies in intestinal integrity, barrier function, digestive capacity and intestinal immune function lead to an increased susceptibility to gastrointestinal inflammatory diseases, such as necrotizing enterocolitis (NEC). The team is applying systems biology approaches to better understand the mechanism by which human milk promotes the maturation of the gastrointestinal tract (GIT) and the associated immune system. Given emerging evidence that milk contains microRNAs in vesicles that remain active upon ingestion by infants for delivery to intestinal cells, researchers posit that these human milk microRNAs play a role in GIT regulation of the immune response in preterm infants. Human milk vesicles will be prepared from milk-donor women and analyzed for microRNA content and their biological anti-inflammatory activity on intestinal cell models and validated in organ culture of the immature human intestine and a mouse NEC model. These studies will provide a proof of concept establishing a role for milk microRNAs in the regulation of intestinal function.

Dr. Deshayne Fell is co-Principal Investigator on The Prevention of Group B Streptococcal (GBS) disease in infants, a $409,276 project funded over three years.
Group B Streptococcus (GBS) disease is a life-threatening bacterial infection that is the leading cause of blood and brain infections in newborns. Despite advances in treatment, many infants with GBS disease die from the infection. Of the babies who survive, up to half suffer long-term effects, including deafness, mild to severe delays in mental function, or paralysis of all four limbs. The highest risk of GBS disease occurs in the first week of life when the infection is acquired from the baby's mother during birth. In order to prevent these early cases, women are screened when they are 35-37 weeks pregnant to see if GBS bacteria are present. Antibiotics are given to all women who are found to have the bacteria, plus women who go into labour prematurely. This reduces cases in the first week of life, but misses some cases and does not prevent cases in older babies. Treating the mother with antibiotics is risky if she has allergies, and might harm the baby by killing beneficial bacteria. The solution may be a vaccine that would be given to women during pregnancy to prevent GBS in the baby. Although vaccines are quite advanced in development, we need to know more about the impact of GBS on babies and the effectiveness of the current screen-and-treat strategy to understand whether a vaccine will be better at preventing cases and reducing healthcare costs. This study aims to fill the evidence gap by linking information about all pregnant women who give birth in Ontario with health care information about their baby to understand how many babies get sick with GBS disease. The results will show how well the current strategy is working, how much it costs and how this compares with the potential benefits and costs of a vaccine. In this way we can find out the best way to protect Canadian children from this devastating infection.
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