Antecedentes

Hoy en día, existe suficiente evidencia para afirmar que, en modelos experimentales, los factores que modifican la citotoxicidad de la huntingtina mutada (Htt), pueden modificar la aparición y progresión de la enfermedad en humanos, y, por lo tanto, pueden ser una buena diana terapeútica para el desarrollo de tratamiento neuroprotectores. Las proteínas que acompañan a la huntingtina y otras proteínas involucradas en el mantenimiento celular pueden ser muy buenos candidatos en este sentido.

Las proteínas no actúan solas en la célula, sino que trabajan como equipos dinámicos y complejos. Es importante poder analizar Proteins do not act alone in the cell: They work as complex and dynamic networks. It is important to analyse HD-relevant information in the context of these gene/protein interaction networks, as this may reveal pivotal disease modifiers and preferred points of therapeutic intervention. In recent years, there has been considerable progress in the execution of genome-scale screens for modifiers of mutant huntingtin toxicity and in the analysis of the large data sets that have been generated. Additionally, several neuroprotective molecules have been identified in model systems, with however the need to elucidate their primary and secondary targets and to prioritise them for preclinical testing. Finally, unbiased genome-wide association studies are being performed to uncover the genetic modifiers of this disease. Therefore, it will be useful to compare these human polymorphism data with biological and chemical data to determine if the two approaches converge onto the same genes and targets.

A major challenge is now to integrate data on genetic and biological modifiers by using network biology approaches to prioritise the best candidate targets and markers. The integrated analysis of neuronal cell responses to the toxic effects of mutant huntingtin will provide strong biological rationales for the modulation of cell death/survival, and will illuminate promising paths to preventive medicine for HD.

Description

The Biological Modifiers and Neuroprevention Working Group aims to improve the HD drug and marker discovery and development processes. The members of the working group contribute with knowledge and data, and collaborate in concerted actions and grant applications. The mode of operation also includes exchange of information with other EHDN working groups (e.g. the Genetic Modifiers, Biomarkers and Neuroprotective Research WGs).

Current projects

The working group focuses on the following topics:

1. Integration of genome-scale information on modification of neurocytotoxicity.
2. Prioritisation of biological modifiers as candidate targets (assessment of disease, drug treatment): rationale, bioinformatic approaches.
3. Target validation based on models of HD pathogenesis and/or human polymorphism data.
4. Neuroprotective drug discovery and development: Chemistry, drug optimisation, drug prioritisation.
5. Funding.

The immediate actions are:

1. To promote the use of network biology to classify and prioritise biological modifiers of mutant Htt cytotoxicity as therapeutic targets or disease markers/modifiers. In this respect, the working group will contribute to target validation and compound development.
2. To uncover and prioritise neuroprotective molecules for evaluation in mice and rats.

Composición

Pueden formar parte de nuestro grupo los expertos en modelos animales, integración de datos, biología en red, genética celular y de ratón, farmacología, así como neurobiólogos, químicos farmacológicos, genetistas clínicos y matemáticos, con objeto de compartir su experiencia investigadora, su práctica y sus proyectos en el marco de acciones concertadas.

Contacto

Líder facilitador

, Denmark