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A phenogenomic approach to identify novel determinants of mitochondrial function

English title A phenogenomic approach to identify novel determinants of mitochondrial function
Applicant Auwerx Johan
Number 133853
Funding scheme R'EQUIP
Research institution Institut interfacultaire de Bioingénierie EPFL - SV - IBI
Institution of higher education EPF Lausanne - EPFL
Main discipline Physiology : other topics
Start/End 01.10.2011 - 30.09.2012
Approved amount 166'000.00
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Keywords (4)

Metabolomics; Metabolic Diseases; Systems genetics; Diabetes

Lay Summary (English)

Lead
Lay summary
Obesity, type 2 diabetes, hyperlipidemia, hypertension, and their complications, such as atherosclerosis and coronary heart disease, are all components of the metabolic syndrome, which is quickly becoming one of the leading causes of mortality in developed and developing countries. Like many diseases, the metabolic syndrome is not caused by a single gene mutant but is due to complex interactions of several genes and their allelic variants with diverse environmental factors. To understand the effect of combinations of alleles to a given phenotype is therefore an important step towards an efficient diagnosis and therapy of such complex diseases in general and the metabolic syndrome in particular.
The ultimate goal of our laboratory is to understand the pathogenesis of complex metabolic diseases and use this knowledge to design new therapeutic and preventive strategies to treat these diseases. Past experience has indicated that the use of genetically engineered mouse models (GEMMs) may not always be optimal to elucidate the factors that predispose to the development of complex multifactorial diseases, as they are designed to study the actions of isolated genetic loci and they are thus insufficient to characterize polygenic networks and genetic interactions, that contribute to the pathogenesis of such complex diseases. Hence, to dissect complex genetic traits, experimental models, like mouse genetic reference populations (GRPs), that imitate the genetic structure of human populations are superior. The project that we propose is part of two major efforts at the European (SYSGENET - European systems genetics network for the study of complex genetic human diseases using mouse genetic reference populations) and national (Sinergia application - Towards systems Genetics: phenotyping the BxD ressource) levels aiming to provide insight in the patho-genesis of complex metabolic disorders. In the context of these projects, our laboratory will use a mouse GRP, com-posed of the BxD recombinant inbred (RI) mouse lines, to identify novel genes and gene networks that contribute to mitochondrial homeostasis and metabolic diseases. We will evaluate the susceptibility to metabolic diseases of a panel of about 50 different BxD strains to cardio-metabolic diseases by determining exercise endurance, energy expenditure, cardiac function, body composition and reparation, bone density, glucose tolerance as well as comprehensive blood profile for clinical biochemistry, metabolites and hematology. Two other research groups will evaluate in the same mice cohorts two additional phenotypes, focussed on sleep and brain activity (Franken, UNIL), and hypoglycemia and neuro-glucopenia (Thorens, UNIL) within the framework of the mentioned EU and Swiss programs. This extensive phenotyping effort will be performed in close collaboration with the Center of Phenogenomics (CPG), the mouse functional genomics facility at the EPFL. Although, a vast array of the equipement required for the execution of this project is already in place, additional technology, more in particular a UPLC-mass spectrometry (UPLC-MS) system dedicated to metabolite analysis is mandatory to succesfully achieve our project. The availability of such an UPLC-MS system will enable the quantification of metabolites, such as NAD+/NADH, (phospho) lipids, fatty acids, bile acids etc, all of which reflect the metabolic state of the mitochondrion and/or the cell. These metabolites cannot be measured in a high-througput and acute manner without this technology. Their levels provide precious information about the metabolic state of the animals. The EPFL and the UNIL do at present not have acces to UPLC-MS system dedicated to the analysis of intermediary metabolites. The UPLC-MS system will be operated by the proteomics core facility of the EPFL and therefore also find use with scientists interested in other research fields.
We hence request here financial support to acquire this UPLC-MS system, which is complementary to the existing equipment available at the EPFL and UNIL and which will allow us to successfully achieve our scientific goals, and elucidate the pathophysiological abnormalities leading to the metabolic syndrome.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Publications

Publication
The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.
Cantó Carles, Houtkooper Riekelt H, Pirinen Eija, Youn Dou Y, Oosterveer Maaike H, Cen Yana, Fernandez-Marcos Pablo J, Yamamoto Hiroyasu, Andreux Pénélope A, Cettour-Rose Philippe, Gademann Karl, Rinsch Chris, Schoonjans Kristina, Sauve Anthony A, Auwerx Johan (2012), The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity., in Cell metabolism, 15(6), 838-47.
The metabolic footprint of aging in mice.
Houtkooper Riekelt H, Argmann Carmen, Houten Sander M, Cantó Carles, Jeninga Ellen H, Andreux Pénélope A, Thomas Charles, Doenlen Raphaël, Schoonjans Kristina, Auwerx Johan (2011), The metabolic footprint of aging in mice., in Scientific reports, 1, 134-134.
Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure.
Watanabe Mitsuhiro, Horai Yasushi, Houten Sander M, Morimoto Kohkichi, Sugizaki Taichi, Arita Eri, Mataki Chikage, Sato Hiroyuki, Tanigawara Yusuke, Schoonjans Kristina, Itoh Hiroshi, Auwerx Johan (2011), Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure., in The Journal of biological chemistry, 286(30), 26913-20.
PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.
Bai Péter, Cantó Carles, Oudart Hugues, Brunyánszki Attila, Cen Yana, Thomas Charles, Yamamoto Hiroyasu, Huber Aline, Kiss Borbála, Houtkooper Riekelt H, Schoonjans Kristina, Schreiber Valérie, Sauve Anthony A, Menissier-de Murcia Josiane, Auwerx Johan (2011), PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation., in Cell metabolism, 13(4), 461-8.
PARP-2 regulates SIRT1 expression and whole-body energy expenditure.
Bai Péter, Canto Carles, Brunyánszki Attila, Huber Aline, Szántó Magdolna, Cen Yana, Yamamoto Hiroyasu, Houten Sander M, Kiss Borbala, Oudart Hugues, Gergely Pál, Menissier-de Murcia Josiane, Schreiber Valérie, Sauve Anthony A, Auwerx Johan (2011), PARP-2 regulates SIRT1 expression and whole-body energy expenditure., in Cell metabolism, 13(4), 450-60.

Associated projects

Number Title Start Funding scheme
125487 Characterization of TGR5 signaling in metabolic homeostasis 01.06.2009 Project funding (Div. I-III)
122697 State representation in reward based learning -- from spiking neuron models to psychophysics 01.01.2009 Sinergia
124713 Phenogenomics of the sirtuin gene family 01.04.2009 Project funding (Div. I-III)
125323 Mice with conditional knockouts of orexin receptors in specific neuronal populations involved in the regulation of sleep and arousal 01.06.2009 Project funding (Div. I-III)
128657 Glucose as a central signal to regulate glucose and energy homeostasis 01.10.2009 Project funding (Div. I-III)
120791 Stress and social brain: a focus on the amygdala and the neuroplasticity molecule PSA/NCAM 01.04.2008 Project funding (Div. I-III)
130825 Sleep homeostasis, clock-genes, and glucocorticoid signaling 01.04.2010 Project funding (Div. I-III)
122691 KRAB/KAP1 epigenetic regulation in the control of memory and emotional traits: from mice to humans. 01.12.2008 Sinergia

Abstract

Obesity, type 2 diabetes, hyperlipidemia, hypertension, and their complications, such as atherosclerosis and coronary heart disease, are all components of the metabolic syndrome, which is quickly becoming one of the leading causes of mortality in developed and developing countries. Like many diseases, the metabolic syndrome is not caused by a single gene mutant but is due to complex interactions of several genes and their allelic variants with diverse environmental factors. To understand the effect of combinations of alleles to a given phenotype is therefore an important step towards an efficient diagnosis and therapy of such complex diseases in general and the metabolic syndrome in particular. The ultimate goal of our laboratory is to understand the pathogenesis of complex metabolic diseases and use this knowledge to design new therapeutic and preventive strategies to treat these diseases. Past experience has indicated that the use of genetically engineered mouse models (GEMMs) may not always be optimal to elucidate the factors that predispose to the development of complex multifactorial diseases, as they are designed to study the actions of isolated genetic loci and they are thus insufficient to characterize polygenic networks and genetic interactions, that contribute to the pathogenesis of such complex diseases. Hence, to dissect complex genetic traits, experimental models, like mouse genetic reference populations (GRPs), that imitate the genetic structure of human populations are superior. The project that we propose is part of two major efforts at the European (SYSGENET - European systems genetics network for the study of complex genetic human diseases using mouse genetic reference populations) and national (Sinergia application - Towards systems Genetics: phenotyping the BxD ressource) levels aiming to provide insight in the patho-genesis of complex metabolic disorders. In the context of these projects, our laboratory will use a mouse GRP, com-posed of the BxD recombinant inbred (RI) mouse lines, to identify novel genes and gene networks that contribute to mitochondrial homeostasis and metabolic diseases. We will evaluate the susceptibility to metabolic diseases of a panel of about 50 different BxD strains to cardio-metabolic diseases by determining exercise endurance, energy expenditure, cardiac function, body composition and reparation, bone density, glucose tolerance as well as comprehensive blood profile for clinical biochemistry, metabolites and hematology. Two other research groups will evaluate in the same mice cohorts two additional phenotypes, focussed on sleep and brain activity (Franken, UNIL), and hypoglycemia and neuro-glucopenia (Thorens, UNIL) within the framework of the mentioned EU and Swiss programs. This extensive phenotyping effort will be performed in close collaboration with the Center of Phenogenomics (CPG), the mouse functional genomics facility at the EPFL. Although, a vast array of the equipement required for the execution of this project is already in place, additional technology, more in particular a UPLC-mass spectrometry (UPLC-MS) system dedicated to metabolite analysis is mandatory to succesfully achieve our project. The availability of such an UPLC-MS system will enable the quantification of metabolites, such as NAD+/NADH, (phospho) lipids, fatty acids, bile acids etc, all of which reflect the metabolic state of the mitochondrion and/or the cell. These metabolites cannot be measured in a high-througput and acute manner without this technology. Their levels provide precious information about the metabolic state of the animals. The EPFL and the UNIL do at present not have acces to UPLC-MS system dedicated to the analysis of intermediary metabolites. The UPLC-MS system will be operated by the proteomics core facility of the EPFL and therefore also find use with scientists interested in other research fields. We hence request here financial support to acquire this UPLC-MS system, which is complementary to the existing equipment available at the EPFL and UNIL and which will allow us to successfully achieve our scientific goals, and elucidate the pathophysiological abnormalities leading to the metabolic syndrome.
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