RESUMO
Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).
Assuntos
Modelos Animais , Animais , Alemanha , Camundongos , FenótipoRESUMO
Consistent protocols for the assessment of diastolic and systolic cardiac function to assure the comparability of existing data on preclinical models are missing. Calcineurin transgene (CN) mice are a preclinical model for hypertrophic and failing hearts. We aimed at evaluating left and right ventricular structural and functional remodeling in CN hearts with an optimized phenotyping protocol. We developed a protocol using techniques and indices comparable to those from human diagnostics for comprehensive in vivo cardiac screening using high-frequency echocardiography, Doppler, electrocardiography and cardiac magnetic resonance (CMR) techniques. We measured left and right ventricular dimensions and function, pulmonary and mitral flow pattern and the hearts electrophysiology non-invasively in <1 h per mouse. We found severe biventricular dilation and a drastic decline in performance in accordance with a condition of heart failure (HF), diastolic dysfunction and defects in electrical conduction in 8-week-old calcineurin transgenic mice. Echocardiography of the left ventricle was performed with and without anesthesia. In all cases absolute values on echocardiography compared with CMR were smaller for LV dimension and wall thickness, resulting in higher fractional shorting and ejection fraction. The study protocol described here opens opportunities to assess the added value of combined echocardiography, Doppler, CMR and ECG recording techniques for the diagnosis of biventricular cardiac pathologies i.e. of HF and to study symptom occurrence and disease progression non-invasively in high-throughput. Phenotyping CN hearts revealed new symptom occurrence and allowed insights into the diverse phenotype of hypertrophic failing hearts.
Assuntos
Calcineurina/genética , Cardiomiopatia Hipertrófica/diagnóstico , Insuficiência Cardíaca/diagnóstico , Ensaios de Triagem em Larga Escala/métodos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Direita/diagnóstico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Direita/diagnóstico , Animais , Calcineurina/metabolismo , Cardiomiopatia Hipertrófica/enzimologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia Doppler , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Direita/enzimologia , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Cadeias Pesadas de Miosina/genética , Fenótipo , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/enzimologia , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda , Função Ventricular Direita , Miosinas Ventriculares/genética , Remodelação VentricularRESUMO
Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.