Descripción del proyecto
Nuevos enfoques pueden resolver la cuestión del potencial toxicológico de los metales para la ELA
La esclerosis lateral amiotrófica (ELA) es una enfermedad neuronal que afecta a las células del cerebro y la médula espinal. La pérdida resultante del control muscular no solo afecta a la capacidad de la persona para moverse, sino también para hablar, comer y respirar. Esta enfermedad neurodegenerativa progresiva y mortal no tiene tratamiento ni cura. Los médicos desconocen su causa en la mayoría de los casos y, si bien se ha investigado la exposición a metales tóxicos, los resultados han sido contradictorios. MetALS está volviendo a evaluar los metales tóxicos teniendo en cuenta factores que otros no han analizado. Se evaluarán como un posible biomarcador las proteínas de choque térmico, cuya respuesta es desencadenada por la exposición a metales tóxicos y cuyo metabolismo se encuentra alterado en los pacientes con ELA. Los resultados arrojarán luz sobre la enigmática y letal ELA.
Objetivo
Background: Exposure to toxic metals are proposed as risk factors for amyotrophic lateral sclerosis (ALS). Despite this, evidence remains mixed, with only evidence for lead exposure supported by recent meta-analysis. Many studies neglected that biomarkers may be affected by kidney and liver function. Additionally, the heat shock protein (HSP) response is triggered by toxic metal exposures, and there is evidence for altered HSP metabolism in ALS. Methods: Using available samples (105 ALS cases, 307 controls), blood HSP’s and toxic metal exposures will be measured primarily in urine (inorganic Hg, lead, chromium, aluminium, selenium, zinc, cadmium, copper and manganese). Confounding variables such as kidney and liver function, and bone turnover will be measured. In addition, prospective recruitment of a further 100 cases and 100 controls will be carried out. For prospectively enrolees, repeat blood and urine samples will be taken three-monthly. Statistical analysis: Multivariable logistic regression will be used to compare HSP’s at baseline, while Bayesian models will be used to model correlations between HSP’s and multiple toxic metals. Longitudinal trends will be modelled using Bayesian mixed effects models. Ordinary differential equations will be used to construct elimination kinetics models. Power calculations indicate 90% power to detect an odds ratio of 2.0 at baseline, and 87% to detect longitudinal differences in trend of 15% or more between cases and controls. Impact: MetALS will employ new methodology to generate fresh insights into the role of toxic metals in ALS. MetALS will confirm or refute the finding of HSP’s as biomarkers in ALS, and provide the first insights into longitudinal behaviour of HSP’s as the disease progresses. MetALS will also provide the first combined study of both HSP’s and toxic metal exposure in an ALS cohort. These novel enquiries are expected to provide fresh insights into HSP’s and toxic metal metabolism in ALS.
Ámbito científico
- natural sciencesmathematicspure mathematicsmathematical analysisdifferential equations
- natural scienceschemical sciencesinorganic chemistrytransition metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural scienceschemical sciencesinorganic chemistrypost-transition metals
- medical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis
Programa(s)
Régimen de financiación
MSCA-IF-EF-ST - Standard EFCoordinador
80539 MUNCHEN
Alemania