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Understanding root causes of kidney stones; to help create better therapies

Kidney stones are common costly and painful. Moreover, there are limited effective therapies to help persons with recurrent kidney stone episodes and the efficacy of a common therapy, thiazide diuretics has recently been called into question by a paper in the New England Journal of Medicine. The greatest risk factor for kidney stones is peeing too much calcium, which is called hypercalciuria. This can occur due to a failure of the kidney to hold onto calcium. Previous work from the Alexander laboratory has revealed how the kidney holds onto calcium by a part of the functional unit known as the proximal tubule. This proposal aims to understand how genetic mutations in genes which encode proteins contributing molecular machinery responsible for the proximal tubule to hold onto calcium cause hypercalciuria and an increased risk of kidney stones. We will also test whether persons with these mutations can be effectively treated with the common kidney stone drug, hydrochlorothiazide. We will use cellular and animal models to determine if these mutations alter how calcium is held onto by the kidney. We will also test the ability for hydrochlorothiazide, a kidney stone therapy drug, to lower urinary calcium content in mice lacking the proteins responsible for proximal tubule calcium handling and people with these genetic mutations. These studies will identify new genes that when mutated result in increased urinary calcium content and thus an increased risk for kidney stone formation. Moreover, our work will identify a sub population of kidney stone formers who will not benefit from thiazides i.e. will need another therapy, and thus inform a precision health approach to kidney stone treatment.

Dr. Zamaneh Kassiri

Modulation of endothelial cells to reduce plaque formation, independent from plasma cholesterol levels

Atherosclerosis is the buildup of lipids (fat) in the blood vessel walls. This can block the artery, interrupt the blood flow and cause heart attack or stroke. Atherosclerosis is initiated by damage to the innermost layer of the vessel wall that is in contact with the bloodstream, which consists of a single layer of endothelial cells (ECs) that are organized in a manner similar to cobblestones, forming a tightly controlled barrier controlling the transfer of the material circulating in the blood (including fat, inflammatory cells, etc.) into the vessel wall and the tissue. Damage to the endothelial cells allows a less restricted passage of fat particles and inflammatory cells into the vessel wall, which, along with other factors (oxidative stress, inflammation), causes damage to the arterial wall, attracting more inflammatory cells to this site. The main inflammatory cells are macrophages, which act like ‘garbage collectors’ and swallow the cholesterol/fat particles in the vessel wall to ‘clean up’ the area. But by doing so, they become filled with ‘fat’ and die. The dead fat-filled cells accumulate in the arterial wall, forming atherosclerotic plaques. Our research has identified a protein (ADAM17) that is increased in atherosclerosis. Our preliminary data show that if ADAM17 levels are reduced in ECs, the severity of atherosclerosis is reduced even if the blood cholesterol remains high. We will use genetically modified mice lacking ADAM17 only in ECs to determine the mechanism of its function. We will also investigate how reducing ADAM17 in ECS can beneficially affect other cells in the vessel wall. Finally, we will use custom-made nanoparticles to deliver material (siRNA) to specifically inhibit Adam17 synthesis in ECs (Adam17siRNA), as a treatment for mice with atherosclerosis. Findings from this study will provide a promising novel therapy for patients in whom blood cholesterol-lowering drugs (statins) are not effective or possible.

Dr. Bradley Kerr

Inflammation, plasticity and pain: Examining sex differences in autoimmune related pain

Dr. Chronic pain is a common feature of nearly every autoimmune disease. Multiple Sclerosis (MS) is one example of an autoimmune disease in which chronic pain is a significant burden for people with the disease. The prevalence of autoimmune disease in general is increasing worldwide and more specifically, Canada has some of the highest rates of MS in the world. Autoimmune diseases disproportionately affect women more than men although pain is reported in both sexes. Recent experimental evidence, however, has revealed that the pathways generating pain can be distinct between men and women. In this project grant, our overall goal is to better define how pain is generated between the sexes in autoimmune disease. With this insight, we hope to be able to develop more targeted pain relief therapies that are tailored in a sex-dependent manner to achieve better pain management for those suffering from diseases like MS. To understand pain in autoimmune disease our studies will focus on a mouse model of MS as it is well established in the field and generates a robust pain phenotype with sex specific features. We will conduct experiments that will determine if sex differences in pain generation are dependent on different sex hormones or the chromosomes in the disease. We will then use specific mouse lines in which key elements of the inflammatory pathways activated in autoimmune disease are removed from sensory neurons to better define the pathways used by males and females for pain in this mouse model of MS. Finally, we will examine differences in structural and functional plasticity between the sexes and examine how different treatments affect these measures and their impact on pain.

Dr. Elaine Leslie

The Influence of Selenium on Arsenic Transport Pathways in Human Hepatocytes and Erythrocytes

Hundreds of millions of people world-wide are exposed to the natural element arsenic in their drinking water. This has resulted in a global public health crisis because arsenic causes cancer in humans and is correlated with other adverse health effects including diabetes and vascular disease. In Canada, arsenic “hot-spots” naturally exist with levels in well water potentially exceeding acceptable levels. As a waste product of industry (especially mining), arsenic is also a serious Canadian concern. While reducing human exposure should be a major priority, evidence suggests that humans are susceptible to arsenic-induced disease for decades following cessation of chronic exposure. Furthermore, in many regions, removing exposure is not economically feasible. Thus, strategies for the treatment and prevention of As-induced disease are necessary.

Selenium is an essential trace element which is toxic in excess. Selenium reduces the toxic effects of arsenic in lab animals by increasing its elimination from the body. Low blood selenium levels in humans chronically exposed to arsenic have been associated with increased risk for arsenic-induced disease. Clinical trials for testing the ability of selenium tablets or selenium-enriched diets to prevent arsenic-induced disease have been initiated in arsenic-endemic regions. The study of how selenium modifies the toxicity of arsenic in human tissues has been largely ignored, despite marked differences in arsenic detoxification between humans and lab animals.

Furthermore, selenium comes in many different chemical forms and the best form for supplementation and prevention of arsenic-induced disease is not known. The overall goal of this research is to understand the influence of different forms of selenium on arsenic metabolism and transport in human liver and red blood cells. Ultimately, this information is critical for optimizing human selenium supplementation and for the prevention and treatment of arsenic-induced disease.

Dr. David Olson

Prolonging gestation and improving newborn outcomes with a novel IL-1 receptor modulator

Bacteria and viruses may enter the uterus during pregnancy, causing infection and fetal inflammation. Inflammation can permanently damage the organs of the fetus and cause preterm birth. Although antibiotics can treat the infection, they cannot stop the intrauterine inflammation that hurts the fetus and causes early labour. Our team designed, synthesized, and tested extensively in human tissues and several animal models a very effective novel small molecule inhibitor of the receptor of the cytokine, Interleukin-1 (IL-1), rytvela. Unfortunately, rytvela is unattractive for investors because its composition of matter patent expires this year. This led us to design LIV-010, an IL-1 receptor antagonist that is superior to rytvela and has patent protection until 2041. Guided by thirteen years of experience with rytvela, we are in a strong position to rapidly perform the required preclinical tests for regulatory approval of LIV-010 from the FDA and Health Canada.Our objective is to complete all steps necessary to hold an IND meeting.

Experimental Aims:
1. Use LIV-010 to block the inflammatory response to a bacterial stimulant in a human fetal membrane explant model;
2. Demonstrate that LIV-010 blocks preterm birth in the pregnant mouse better than rytvela and protects the fetus and newborn from inflammatory harm;
3. Perform small animal toxicity and PK/PD studies on LIV-010.

Commercialization Objectives:
A. Validate LIV-010's target product profile;
B. Clarify the global patent position for LIV-010;
C. Demonstrate investor and market interest in LIV-010 by derisking it for safety and efficacy profiles;
D. Scale-up LIV-010 production;
E. Hold an IND meeting with Health Canada and the FDA.

Significance: An IND meeting will increase the value of LIV-010 and will stimulate further investment into its development for use in patients. If successful, LIV-010 will be the most significant advance in fetal/newborn therapeutics since surfactant.

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