Akademik Veri Yönetim Sistemi
Gülhan R. (Yürütücü), Günal D., Aydın Omay B., Tapşın Güllüoğlu S., Ömercikoğlu Özden H., Güllüoğlu Ş.
TÜBİTAK Projesi, 2024 - 2027
Biomarker and drug target discovery in Alzheimer’s disease (AD) has been largely focused on proteomics. Proteomics analyses have led to potential blood biomarkers for AD and further may be implemented to identify prodromal AD (high amyloid β status with mild cognitive impairment, i.e. are likely to convert to AD). However, the most commonly used biomarker, amyloid β or tau derivatives, are possibly not the furthest upstream marker. We hypothesize the existence of AD-specific markers further upstream of amyloid β, tau and other proteomics markers. Several metabolomics studies of AD patients have been carried out before and identified diverse markers. Our interdisciplinary project proposal will cover a series of important gaps:
1) Inclusion of prodromal AD samples in addition to AD samples.
2) Complementary to standard metabolomics analyses, we will additionally use a bespoke, cutting-edge technology developed by metabolomics expert Dr. Daniel Globisch, which will allow for the identification of previously unknown metabolites (thus not in commercial libraries and would otherwise go undetected).
4) Metabolomics will be supplemented with advanced glycomics, exploring the changes of glycans in the blood or the CSF. Both free and cell-associated (i.e., those expressed by white blood cells) will be analyzed, utilizing targeted and high-throughput biochemical and omics analyses. Alteration of glycans will be utilized for biomarker and drug target discovery.
4) Investigation of transnational cohorts from Sweden, Spain, and Turkey to eliminate the risk of identifying markers based on local environmental and genetic factors.
5) We will use cutting-edge metabolic modelling and machine learning algorithms on the metabolomics and glycan biomarkers to identify profiles of plasma and CSF metabolites that are specific to prodromal AD and AD.
6) Validation of each hit of a candidate biomarker or drug target by purchasing or synthesizing the identified compounds and validating the chemical structure at the highest confidence level. The consortium will select the most promising hits to investigate based on evidence generated during the analyses.
6) Comparison to metabolomics of animal models, to identify which metabolic or glycan markers or profile of markers that can be further investigated in animal models of AD for drug discovery.
7) Druggability assessment of newly identified drug targets will be conducted utilizing target-specific functional bioassays using in vitro cell culture models.
Analysis of the prodromal AD stage is important, as patients receiving an AD diagnosis are already heavily affected by the disease. In addition, this study aims to identify early markers at the stage of amyloid positive mild cognitive impairment, which would enable early intervention. Our team is highly multi-disciplinary, consisting of a pre-clinical researcher specializing in animal models, a neurologist with knowledge of AD and access to patient samples and cognitive data, a metabolomics expert with in-depth chemistry expertise, drug discovery scientist focusing on glycans and a metabolic modelling expert. We believe that by integrating all these skills, we will uncover previously unknown metabolic clues for AD development than any previous study published hitherto. This has the potential to identify new drug targets and to develop new diagnostics for the timely diagnosis of AD at the onset. This would reduce the burden of patients and the costs of healthcare systems worldwide.