Reference number : GC-2017-Q1-01793, amendment number : , agreement type : G, recipient legal name : Seubert, John (University of Alberta), recipient country : CA, recipient province : nan, recipient city : Alberta, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : OVERVIEW 
Biological aging is an inevitable part of life that has intrigued individuals for millennia. While we comprehend the aging process is a progressive decline in biological systems, our understanding of the molecular, biochemical and physiological mechanisms involved is limited. Current evidence suggests mitochondrial dysfunction is an overarching mechanism associated with aging. Exposure to environmental toxins can compromise mitochondrial quality potentially causing premature aging. Lipopolysaccharide (LPS) is an integral component of the cell wall in gram-negative bacteria. Biological effects produced by LPS are multiple and complex; however, little is known regarding their effect on mitochondrial quality and aging. The heart is a highly metabolic organ that requires a healthy pool of mitochondria to ensure cellular homeostasis making it vulnerable to mitochondrial damage. Our goal is to investigate the impact of environmental toxins, such as LPS, on mitochondrial quality and the relationship to aging. The long-term objective is to discover how mitochondrial quality changes with age and how this relates to age-related decline in cardiac function. We hypothesize that chronic exposure to low doses of LPS will damage mitochondrial quality resulting in decreased cardiac function, similar to changes observed during aging. 
 SPECIFIC GOALS 
 AIM 1 To investigate the effect of chronic exposure to LPS on cardiac mitochondria and aging. This aim proposes to establish the time course and characterization of how chronic treatment with LPS impacts mitochondrial quality and cardiac aging. We will expose mice to low doses of LPS to explore changes to mitochondria and cardiac function over a significant portion of their lifespan. 
 AIM 2 To determine how tolerance to LPS impacts cardiac aging. The transmembrane receptor responsible for LPS sensing and signal transduction is the TLR-4. This aim will focus on how down regulating TLR-mediated signaling impacts LPS-induced effects on cardiac mitochondrial quality and aging. Disrupting TLR-4 mediated signaling will help us better understand important pathways connecting LPS signaling to mitochondrial and cardiac dysfunction and aging. 
 AIM 3 To explore the effect of a germ free environment on cardiac aging. Axenic (germ free) mice together with a germ environment will be utilized as an in vivo model to dissect out interactions between the host and LPS. This approach will allow us to explore basic mechanisms of how environmental toxins impact mitochondrial quality as well some fundamental insight into unique processes of biological aging isolated from microflora. 
 SIGNIFICANCE 
The proposed research will provide new insight into understanding how decreased mitochondrial quality effects cardiac aging. Moreover, it will provide new information regarding the mechanisms of LPS induced damage to mitochondrial quality and a cardiac aging phenotype., program purpose french : OVERVIEW 
Biological aging is an inevitable part of life that has intrigued individuals for millennia. While we comprehend the aging process is a progressive decline in biological systems, our understanding of the molecular, biochemical and physiological mechanisms involved is limited. Current evidence suggests mitochondrial dysfunction is an overarching mechanism associated with aging. Exposure to environmental toxins can compromise mitochondrial quality potentially causing premature aging. Lipopolysaccharide (LPS) is an integral component of the cell wall in gram-negative bacteria. Biological effects produced by LPS are multiple and complex; however, little is known regarding their effect on mitochondrial quality and aging. The heart is a highly metabolic organ that requires a healthy pool of mitochondria to ensure cellular homeostasis making it vulnerable to mitochondrial damage. Our goal is to investigate the impact of environmental toxins, such as LPS, on mitochondrial quality and the relationship to aging. The long-term objective is to discover how mitochondrial quality changes with age and how this relates to age-related decline in cardiac function. We hypothesize that chronic exposure to low doses of LPS will damage mitochondrial quality resulting in decreased cardiac function, similar to changes observed during aging. 
 SPECIFIC GOALS 
 AIM 1 To investigate the effect of chronic exposure to LPS on cardiac mitochondria and aging. This aim proposes to establish the time course and characterization of how chronic treatment with LPS impacts mitochondrial quality and cardiac aging. We will expose mice to low doses of LPS to explore changes to mitochondria and cardiac function over a significant portion of their lifespan. 
 AIM 2 To determine how tolerance to LPS impacts cardiac aging. The transmembrane receptor responsible for LPS sensing and signal transduction is the TLR-4. This aim will focus on how down regulating TLR-mediated signaling impacts LPS-induced effects on cardiac mitochondrial quality and aging. Disrupting TLR-4 mediated signaling will help us better understand important pathways connecting LPS signaling to mitochondrial and cardiac dysfunction and aging. 
 AIM 3 To explore the effect of a germ free environment on cardiac aging. Axenic (germ free) mice together with a germ environment will be utilized as an in vivo model to dissect out interactions between the host and LPS. This approach will allow us to explore basic mechanisms of how environmental toxins impact mitochondrial quality as well some fundamental insight into unique processes of biological aging isolated from microflora. 
 SIGNIFICANCE 
The proposed research will provide new insight into understanding how decreased mitochondrial quality effects cardiac aging. Moreover, it will provide new information regarding the mechanisms of LPS induced damage to mitochondrial quality and a cardiac aging phenotype., agreement title english : Investigating how the environmental toxicant LPS impacts mitochondrial quality control and the biological aging process in heart, agreement title french : Investigating how the environmental toxicant LPS impacts mitochondrial quality control and the biological aging process in heart, agreement number : RGPIN, agreement value : 25000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2018-2019), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada