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Investigating the pharmacokinetic properties of toxic metals and heat shock proteins as risk factors in Amyotrophic Lateral Sclerosis

Project description

New approaches may settle the question of metal toxicity's potential role in ALS

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease affecting cells in the brain and spinal cord. The resulting loss of muscle control affects not only a person's ability to move but also to speak, eat, and breathe. This fatal progressive neurodegenerative disease has no treatment and no cure. Doctors do not know what causes it in most cases but toxic metal exposure has been investigated with contradictory results. MetALS is re-evaluating toxic metals, looking at factors that others have not. Heat shock proteins, whose response is triggered by toxic metal exposure and whose metabolism is altered in ALS, will be evaluated as a potential biomarker. Outcomes will shed light on the enigmatic and lethal ALS.

Objective

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.

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MSCA-IF-EF-ST - Standard EF

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2018

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Coordinator

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 162 806,40
Address
GESCHWISTER SCHOLL PLATZ 1
80539 MUNCHEN
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 162 806,40
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