Revealing the molecular mechanisms of neurodegenerative diseases using the biological networks

Lead Supervisor
Professor Adil Mardinoglu
Professor of Systems Biology
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London
adil.mardinoglu@kcl.ac.uk

Project Details

Neurodegenerative diseases (NDDs) are a broad range of complex neurological disorders. The World Health Organization (WHO) estimates that by 2040, NDDs including cognitive-compromising disorders (such as Alzheimer’s disease (AD) as well as conditions compromising motor functions (for instance, Parkinson’s disease (PD)), will become the second leading cause of death worldwide after cardiovascular disease (CVD), thus overtaking cancer in terms of mortality rate. In order to develop efficient treatment strategies for AD and PD, we propose a BRAINMAP project to generate a high-resolution complete molecular map of the human, brain based on proteomics (single-cell, region-specific and bulk-tissue) and transcriptomics (single-cell, region-specific and bulk-tissue) data.

This proposal aims to allow a systematic analysis of the human brain using integration of various technology platforms to create a molecular map of the human brain with a focus on analysing protein and transcript expression levels in various cell types and regions. Novel drug targets and biomarkers that will be used in the early detection and stratification of the patients will be identified using these tissue specific molecular maps.

The project takes advantage of the large resources of more than 50,000 antibodies generated within the frame-work of the Human Protein Atlas and the single-cell transcriptomics data generated in the Human Cell Atlas program. The integration of transcriptomics with the proteomics data allows the exploration of gene/protein expression patterns with single-cell resolution in the context of neighboring cells.

The data will be used for cell topological analysis, systems modelling and data integration to create a brain-centred knowledge resource of gene and protein expression in the human brain. All data and the generated (cell-type/region/whole-brain specific) networks will be publicly available through a dedicated open-access BRAINMAP portal (http://inetmodels.com/brain) developed as part of the project. It will be publicly available in an open access manner adopting the FAIR Data Principles. The overall objective is the generation of an interactive online knowledge resource and network portal that links proteins, cellular networks and functions in the human brain.

The project involves six work packages with clearly defined objectives and deliverables.

Datasets

The current research proposal included the analysis of brain tissue from human. The transcriptomics and proteomics data have been generated using the resources provided by the international collaborators. We do not seek any aim for the collection of tissues or the generation of transcriptomics and proteomics data. Human tissue samples used for protein and mRNA expression analyses were collected and handled in accordance with Swedish laws and regulation and obtained from the Department of Pathology, Uppsala University Hospital, Uppsala, Sweden as part of the sample collection governed by the Uppsala Biobank (http://www.uppsalabiobank.uu.se/en/). All human tissue samples used in the present study were anonymized in accordance with approval and advisory report from the Uppsala Ethical Review Board (Reference # 2002-577, 2005-338 and 2007-159 (protein) and 2011-473 (RNA)), and consequently the need for informed consent was waived by the ethics committee. Transcriptomics and proteomics data have been generated in the HPA program and the data have been shared with us.

Keywords

Neurodegenerative diseases, systems modelling, integrated multiomics, molecular map, biological networks