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Project
Neuro-TARGET : integrated platform for target identification, validation and drug discovery with applications for neurodegenerative diseases. (IWT420)
In light of the ever increasing incidence of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, in our ageing population in the western world, we propose to establish an integrated platform for target identification, validation and drug discovery to foster the development of novel therapeutics for neurodegeneration. Using cutting-edge technologies we will identify new disease-related genes from human biosamples and humanized yeast models. Generic and strategic research tools for identification and validation of novel targets will be developed. Functional genomics will be carried out in different model systems, including yeast, mammalian neuronal cell lines and rodent models to unravel the pathogenic pathways and potential interactions of the corresponding proteins with the objective to validate key molecular events and therapeutic targets. Targets that define the onset of pathology will constitute prime markers for early diagnosis. Both validated targets and new assays will foster a drug discovery platform. Although most of the generated models and tools are generic in nature, in this project we will focus primarily on applications for Parkinson's disease (PD).
Our proposal is subdivided in 4 work packages.
WP1: Identification of novel genes and targets
Novel potential disease targets will be provided to the project from two different sources.
First, we will exploit the genetic power of humanized yeast model systems to identify novel genes modulating _-synuclein (_-SYN) toxicity and to elucidate the pathogenic pathways of 2 recently identified familial PD genes, PINK1 and LRRK2.
Second, we will identify new genes linked to PD from human biosamples using a dual strategy. We will identify novel chromosomal loci and causal genes for PD using a positional cloning strategy in PD families. In addition we will perform genetic association studies in a large group of PD patients to identify novel genetic risk and protective factors, focusing on variants influencing the expression of known PD genes.
WP2 Development of novel generic technologies, assays and disease models
Validation of new disease targets and testing of novel therapeutic strategies is highly dependent on the availability of quantitative, reliable and sensitive technologies in cell culture and in animal models.
* We will develop quantifiable assays to correlate _-SYN phosphorylation and aggregation with cell death in yeast
* We will establish a medium-throughput, multiparametric assay using a high-content analyzer to measure _-SYN aggregation, apoptosis, mitochondrial and proteasomal dysfunction and oxidative stress in neuronal cell lines.
* We will perform a kinase substrate search using a novel "chemical genetic" strategy to identify substrates of two PD-linked kinases, PINK1 and LRRK2.
* We will generate two in vivo reporter systems to monitor respectively proteasomal function and apoptosis in the rodent brain.
* We will combine (lenti)viral vector technology with micro-RNA based technology to generate novel transgenic mouse and rat models.
* Novel disease models will be generated for each novel disease-related gene identified in WP1
WP3: Platform for target validation
In the newly developed model systems (WP2) we will validate novel targets from WP1 as well as a number of previously identified, non-validated targets. Initial target validation will be performed in yeast and in mammalian cells. For a limited set of genes final validation will be done in rodent brain.
WP4: Platform for drug discovery
For each validated target an assay based on a screenable phenotype in yeast or in cell culture will be established for drug testing. We will initiate a drug discovery pipeline in newly developed and available model systems in yeast and neuronal cell lines to identify novel hits from the CD3 library. Medicinal chemistry will support hit to lead development. Toxicology and pharmacokinetics studies will further improve the efficacy of the ligands. We will also incorporate in silico-selected ligands in the drug discovery program. The final stage will consist of testing selected novel compounds in the available animal models and in vivo ADMETox studies.
In conclusion, the NEURO-TARGET consortium offers an integrated 'start-to-end' approach to identify novel targets and develop novel models and therapeutics to combat Parkinson's Disease and related neurodegenerative disorders.
Our proposal is subdivided in 4 work packages.
WP1: Identification of novel genes and targets
Novel potential disease targets will be provided to the project from two different sources.
First, we will exploit the genetic power of humanized yeast model systems to identify novel genes modulating _-synuclein (_-SYN) toxicity and to elucidate the pathogenic pathways of 2 recently identified familial PD genes, PINK1 and LRRK2.
Second, we will identify new genes linked to PD from human biosamples using a dual strategy. We will identify novel chromosomal loci and causal genes for PD using a positional cloning strategy in PD families. In addition we will perform genetic association studies in a large group of PD patients to identify novel genetic risk and protective factors, focusing on variants influencing the expression of known PD genes.
WP2 Development of novel generic technologies, assays and disease models
Validation of new disease targets and testing of novel therapeutic strategies is highly dependent on the availability of quantitative, reliable and sensitive technologies in cell culture and in animal models.
* We will develop quantifiable assays to correlate _-SYN phosphorylation and aggregation with cell death in yeast
* We will establish a medium-throughput, multiparametric assay using a high-content analyzer to measure _-SYN aggregation, apoptosis, mitochondrial and proteasomal dysfunction and oxidative stress in neuronal cell lines.
* We will perform a kinase substrate search using a novel "chemical genetic" strategy to identify substrates of two PD-linked kinases, PINK1 and LRRK2.
* We will generate two in vivo reporter systems to monitor respectively proteasomal function and apoptosis in the rodent brain.
* We will combine (lenti)viral vector technology with micro-RNA based technology to generate novel transgenic mouse and rat models.
* Novel disease models will be generated for each novel disease-related gene identified in WP1
WP3: Platform for target validation
In the newly developed model systems (WP2) we will validate novel targets from WP1 as well as a number of previously identified, non-validated targets. Initial target validation will be performed in yeast and in mammalian cells. For a limited set of genes final validation will be done in rodent brain.
WP4: Platform for drug discovery
For each validated target an assay based on a screenable phenotype in yeast or in cell culture will be established for drug testing. We will initiate a drug discovery pipeline in newly developed and available model systems in yeast and neuronal cell lines to identify novel hits from the CD3 library. Medicinal chemistry will support hit to lead development. Toxicology and pharmacokinetics studies will further improve the efficacy of the ligands. We will also incorporate in silico-selected ligands in the drug discovery program. The final stage will consist of testing selected novel compounds in the available animal models and in vivo ADMETox studies.
In conclusion, the NEURO-TARGET consortium offers an integrated 'start-to-end' approach to identify novel targets and develop novel models and therapeutics to combat Parkinson's Disease and related neurodegenerative disorders.
Date:1 Jan 2009 → 31 Dec 2012
Keywords:Parkinson's disease, drug discovery, neuroscience
Disciplines:Basic sciences, Pharmaceutical sciences