The overall objective of the Mouse Management and Pathology Core (Core B) is to raise, maintain, and provide cohorts of specific pathogen-free and genetically standardized p66Shc-/- knockout mice for all research projects in this program project. Also, the core will raise and maintain mice on calorie-restricted, low-carbohydrate and high-carbohydrate/high-fat diets and provide those mice and their tissues to the research projects in order to assess age-related metabolic consequences and clinical and anatomic pathologies. All mice analyzed will be on a congenic C57BL/6J genetic background and maintained in a mouse dedicated vivarium under barrier conditions. Core B will accomplish these objectives using relevant resources and technical expertise drawn primarily from the UC Davis Mouse Biology Program. Core B will fulfill the following two Specific Aims:
Specific Aim 1 : Provide p66Shc-/- and littermate control mice at selected stages of life ("cross-section analysis") in response to caloric restriction diet. p66Shc-/- and wild-type control mice will be bred, and sampled at specific intervals for biochemical and microarray analysis in Projects 1 and 2. The results of this Aim will reveal the extent to which She alters the metabolic response to sustained caloric restriction.
Specific Aim 2 : Provide p66Shc-/- and littermate control mice for lifespan analysis and assess clinical and anatomic pathologies in response to high-fat/high-carbohydrate and low-carbohydrate diets. Similarly, p66Shc-/- mice resist high-fat diets and are expected to have increased lifespan in that condition, and so an investigation of lifespan-limiting pathology in that condition is important.
Aim 2 will serve the hypothesis that a low-carbohydrate thus the underlying diet mimics the effects of caloric restriction and She-deficiency extends lifespan, and pathology will be investigated.
Obesity and diabetes are massive problems for Westerners who live in a high-fat diet environment. The program project has shown that She knockout mice resist both obesity and diabetes, and, as an animal core, Core B provides highly standardized, genetically characterized and clean mice for further studies of mechanism, and interventions to promote healthy aging.
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|Tomilov, Alexey; Bettaieb, Ahmed; Kim, Kyoungmi et al. (2014) Shc depletion stimulates brown fat activity in vivo and in vitro. Aging Cell 13:1049-58|
|Patron, Maria; Checchetto, Vanessa; Raffaello, Anna et al. (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53:726-37|
|Sahdeo, Sunil; Tomilov, Alexey; Komachi, Kelly et al. (2014) High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. Mitochondrion 17:116-25|
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|Granatiero, Veronica; Patron, Maria; Tosatto, Anna et al. (2014) The use of aequorin and its variants for Ca2+ measurements. Cold Spring Harb Protoc 2014:9-16|
|Stern, Jennifer H; Kim, Kyoungmi; Ramsey, Jon J (2014) The influence of shc proteins on the whole body energetic response to calorie restriction initiated in 3-month-old mice. ISRN Nutr 2014:562075|
|Bock, Fabian; Shahzad, Khurrum; Wang, Hongjie et al. (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci U S A 110:648-53|
|Chen, Yana; Hagopian, Kevork; Bibus, Douglas et al. (2013) The influence of dietary lipid composition on liver mitochondria from mice following 1 month of calorie restriction. Biosci Rep 33:83-95|
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