Descrizione del progetto
Nuovi approcci potrebbero risolvere la questione del potenziale ruolo della tossicità dei metalli nella SLA
La sclerosi laterale amiotrofica (SLA) è una malattia dei motoneuroni che colpisce le cellule del cervello e del midollo spinale. La conseguente perdita di controllo muscolare influisce non solo sulla capacità di una persona di muoversi, ma anche di parlare, mangiare e respirare. Questa malattia neurodegenerativa progressiva fatale non ha trattamento né cura. Nella maggior parte dei casi, i medici non ne conoscono la causa ma è stata studiata l’esposizione ai metalli tossici, seppure con risultati contraddittori. Il progetto MetALS sta riesaminando i metalli tossici, osservando fattori che altri non hanno. Le proteine dello shock termico, la cui risposta è innescata dall’esposizione a metalli tossici e il cui metabolismo è alterato nella SLA, saranno valutate come potenziale biomarcatore. I risultati faranno luce sulla enigmatica e letale SLA.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
80539 MUNCHEN
Germania