Reference number : GC-2017-Q1-02723, amendment number : , agreement type : G, recipient legal name : Zhang, Ji (McGill University)|Zhang, Ji (Université McGill), recipient country : CA, recipient province : nan, recipient city : Quebec|Québec, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : While eating patterns can help people to achieve/maintain good health, not much is known about how diet affects basic cellular function and physiological ability. As sensing pain is essential for an individual to adapt to its environment and to avoid damage, we want to understand whether (and how) what we eat affects how we feel. We propose a research program with long term objectives to investigate the impact of dietary products on physiological nociceptive response. 
Salt is an essential nutrient required for normal functioning of many types of cells, but it has pro-inflammatory properties. High salt diet (HSD) seen in daily life in westernized society is also a potential candidate disturbing the gut microbiota. In this 5-year research proposal, we will feed healthy C57BL/6 male and female mice with HSD (4% NaCl in chow and 1% NaCl in water) for 3 months to investigate how HSD affects physiological nociceptive response. We will target macrophages (M&Oslash;s) in the gut and in the nervous system to dissect underlying mechanisms. Our hypothesis is that HSD polarizes gut M&Oslash;s into pro-inflammatory status, contributing to the development of systemic inflammation, which in turn promotes the activation of M&Oslash;s/microglia along the pain transmission pathway, leading to enhanced pain sensitivity. 
Aim 1: Uncover dietary modulation of M&Oslash; identity by analyzing the features of M&Oslash;s in the gut and M&Oslash;s/microglia along the pain transmission pathway 
Aim 2: Reveal whether HSD alters nociceptive response to various stimuli by performing a series of behavioral tests 
Aim 3: Dissect underlying mechanisms of HSD-induced alteration in pain sensitivity by: 
3.1 Depleting M&Oslash;s/microglia to understand whether HSD-induced alteration in nociceptive pain behavior requires the participation of M&Oslash;s. 
3.2 Applying HSD to CCD2-/- mice to understand the role of gut M&Oslash;s in diet-induced alteration of the immune system and nociception. Since gut M&Oslash;s at adulthood are derived exclusively from CCR2-mediated recruitment and CCR2-/- mice have a considerable deficit in gut M&Oslash;s. 
3.3 Disrupting gut microbiota in mice under HSD with broad spectrum antibiotics to unveil the requirement of gut microbiota in HSD-induced changes in M&Oslash; identity and pain sensitivity. 
This research will not only advance significantly our knowledge on how dietary lifestyle alters physiological homeostasis and fundamental functions, but also allow us to pioneer the involvement of microbiota in sensory behavior which is at its very beginning stage., program purpose french : While eating patterns can help people to achieve/maintain good health, not much is known about how diet affects basic cellular function and physiological ability. As sensing pain is essential for an individual to adapt to its environment and to avoid damage, we want to understand whether (and how) what we eat affects how we feel. We propose a research program with long term objectives to investigate the impact of dietary products on physiological nociceptive response. 
Salt is an essential nutrient required for normal functioning of many types of cells, but it has pro-inflammatory properties. High salt diet (HSD) seen in daily life in westernized society is also a potential candidate disturbing the gut microbiota. In this 5-year research proposal, we will feed healthy C57BL/6 male and female mice with HSD (4% NaCl in chow and 1% NaCl in water) for 3 months to investigate how HSD affects physiological nociceptive response. We will target macrophages (M&Oslash;s) in the gut and in the nervous system to dissect underlying mechanisms. Our hypothesis is that HSD polarizes gut M&Oslash;s into pro-inflammatory status, contributing to the development of systemic inflammation, which in turn promotes the activation of M&Oslash;s/microglia along the pain transmission pathway, leading to enhanced pain sensitivity. 
Aim 1: Uncover dietary modulation of M&Oslash; identity by analyzing the features of M&Oslash;s in the gut and M&Oslash;s/microglia along the pain transmission pathway 
Aim 2: Reveal whether HSD alters nociceptive response to various stimuli by performing a series of behavioral tests 
Aim 3: Dissect underlying mechanisms of HSD-induced alteration in pain sensitivity by: 
3.1 Depleting M&Oslash;s/microglia to understand whether HSD-induced alteration in nociceptive pain behavior requires the participation of M&Oslash;s. 
3.2 Applying HSD to CCD2-/- mice to understand the role of gut M&Oslash;s in diet-induced alteration of the immune system and nociception. Since gut M&Oslash;s at adulthood are derived exclusively from CCR2-mediated recruitment and CCR2-/- mice have a considerable deficit in gut M&Oslash;s. 
3.3 Disrupting gut microbiota in mice under HSD with broad spectrum antibiotics to unveil the requirement of gut microbiota in HSD-induced changes in M&Oslash; identity and pain sensitivity. 
This research will not only advance significantly our knowledge on how dietary lifestyle alters physiological homeostasis and fundamental functions, but also allow us to pioneer the involvement of microbiota in sensory behavior which is at its very beginning stage., agreement title english : Dietary modulation of macrophage identity: potential impact on nociceptive sensory response, agreement title french : Dietary modulation of macrophage identity: potential impact on nociceptive sensory response, agreement number : RGPIN, agreement value : 160000.0, 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 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), 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