Novel biomarkers

Description

Stroke and MS are complex diseases with several mechanisms contributing sequentially or simultaneously to their pathophysiology and progression. Even though diagnosis of the acute stroke is not considered problematic, MS with variable clinical presentations has no diagnostic laboratory test. Importantly, while MRI is a valuable tool to follow up the progression of these diseases, there are no biomarkers that could be used to dissect the contribution of various disease mechanisms, preventing therefore the stratification of subcategories for MS and of disease stages and prediction of disease course of MS. Moreover, the lack of mechanism-dependent biomarkers impairs treatment selection and evaluation of prognosis for treatment success, and especially prevents the evaluation of novel therapeutics. Though it is unlikely that one biomarker alone could function as a true surrogate, biomarkers can provide insight into the mechanism of action of a drug and could suffice for the pre-screening of prospective therapeutics. In this ITN partner 10 will develop and test novel biomarker approaches using MRI and micro-PET imaging as well as screens of body fluids (blood, CSF, urine) to detect alterations in key components of immune response and inflammation in MS and stroke. These components include inflammatory modulators, mediators of oxidative and nitrosative stress as well as lipid or protein modifications secondary to specific inflammatory and stress responses of various cell types involved in MS and stroke pathogenesis and recovery. The imaging technologies and body fluid analysis methods will be employed for the stroke and MS models made available by partners 2 and 12 and taking advantage of the modern imaging platforms made available by partners 2, 7, and 8. The ESR will work at the laboratories of partner 7 under supervision of partners 10 and 7.

Publications

• Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10: 719-26
• Semenova MM, Mäki-Hokkonen AM, Cao J, Komarovski V, Forsberg KM, Koistinaho M, Coffey ET, Courtney MJ (2007) Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death. Nat Neurosci 10: 436-43 

Tasks and methodology

• To explore markers of inflammation (e.g. infiltration of inflammatory cells and activation status of inflammatory cells) using MRI and micro-PET in animal models of stroke and MS
• To study markers of inflammation and lipid peroxidation using biochemical methods in CNS tissue, CSF, blood and/or urine and to correlate these findings to imaging data in animal models of stroke and MS
• To study the relationship of above biomarkers/ surrogate markers to disease progression in models of stroke and MS (made available by other partners) and establish correlation of these markers to therapeutic efficacy of known immunomodulatory compounds and novel therapeutics under development (made available by Medeia Therapeutics)

Planned secondment

Partner 2, Spanish National Research Council, Evaluation of new tools to track BMDM by 2-photon microscopy, 10 month