InfrafrontierGR/Phenotypos focuses on expanding the existing InfrafrontierGR pipelines with phenotypic screens for modifiers of Neurological and Cognitive Deficits as well as Metabolic (e.g. Obesity, Type II Diabetes) and cardiovascular syndromes.
The “Phenotypos” addition of new disease filters is accompanied by service platforms capable of analyzing specific behavioral, metabolic & cardiovascular disease traits. Furthermore, these platforms are essential for complete description of any phenotype and disease state, including inflammatory diseases and cancer. Conversely, the existing immunological, histopathological, molecular and imaging phenotypic modalities of INFRAFRONTIER-GR are essential for the analysis of all phenotypes, including complex neurological syndromes or diabetes. The requirement for platform expansion also stems from the increasing research interest on the cross-comparison of genetic and cellular mechanisms underlying the range of diseases targeted by INFRAFRONTIER-GR/Phenotypos.
Phenotypos covers these new disease filters by including the following models in its pipeline:
Models of Neurodegenerative and Cognitive disorders: These include: (i) the Davis tauopathy mouse, which models aspects of Alzheimer’s and Picks disease. These mice lack all endogenous Tau, but carry the entire human locus and develop progressively intensifying age-dependent cognitive deficits. (ii) models of Neurofibromatosis 1, an autosomal dominant human nervous system genetic disorder. Similar with patients, these conditional knock-outs exhibit deficient spatial learning and memory, attention and motor coordination. (iii) Mice lacking the anaplastic lymphoma kinase (Alk), which exhibit enhanced performance in certain cognitive tests. (iv) Mouse models of Fragile X syndrome, a genetic disease distinguished by mental retardation, learning deficits, decrease sociability and social interactions. (v) Alpha-synuclein mutants that model Parkinson’s disease, degeneration in the CNS, motor dysfunction and dopamine malfunction. Furthermore, given that many behavioral platforms have been established and characterized in the rat model, which lacks strong genetics, novel findings from the rat platform will be modeled and genetically analyzed in the mouse.
Models of Metabolic Syndromes: These include: (i) Models of high-fat diet displaying impaired glucose tolerance (IGT) and type 2 diabetes, (ii) Leptin deficient mice that become profoundly obese due to loss of appetite control, (iii) Apolipoprotein E and LDL Receptor deficient models of atherosclerosis developing lesions with age because of hypercholesterolemia, (iv) Models of assessing the connection between chronic inflammation and metabolic aberrations, such as TNF overexpressors, which develop organ-specific inflammation, diabetes, inflammatory bowel disease or insulin resistance and mice lacking IRS2 or stress hormones.
Models of cardiovascular diseases and vascular dysfunction: Models to study heart failure include i) the desmin knockout mouse developing cardiac degeneration and cardiomyopathy, ii) Knock-out mice of complement system components (C3. C5. C5a, a2), which modulate innate immunity and result in heart defects. Models to study vascular dysfunction include i) mice with endothelial deletions of integrin modulators affecting adhesion to blood vessels, which display a range of vascular defects, and ii) vascular-induced retinopathies, modeled by exposure to different oxygen tension (hyperoxia/hypoxia) thus inducing rapid development of new blood vessels similarly to diabetic or genetic retinopathies.