European Commission logo
español español
CORDIS - Resultados de investigaciones de la UE
CORDIS

Development of novel computational biology pipeline for the efficient classification of titin SNPs for clinical use

Objetivo

Mutations in the giant muscle protein titin are a major cause of heart disorders in human populations. Routine DNA screening of patient cohorts is now becoming feasible, with a staggering number of titin truncations and missense single nucleotide polymorphisms (mSNPs) rapidly accumulating in genomics databases (>17,000 mSNPs). While the link between titin truncation and disease is now becoming clarified, detecting the pathogenic potential of mSNPs remains a substantial challenge. In mSNPs classification, bioinformatics evaluation is a necessary first filtering step, but existing predictors are poorly reliable. To address this problem, we aim to develop a new titin-centric scoring function that predicts the mechanistic effect of an mSNP exchange in the titin protein by considering the specific characteristics of its poly-domain chain. For this work, we will build a medium-throughput molecular diagnostic pipeline that harvest existent structural models of titin components in estimating mSNPs-induced changes in free energy and conformational dynamics in the protein. Calculations will be benchmarked against experimentally obtained biophysical and biochemical data. To develop this methodology, we will use a clinically pertinent training set of 75 mSNPs. However, in a subsequent step, stable predictions will be extrapolated to the rest of the titin chain by exploiting the repetition of structural and functional loci within the chain. A titin map of vulnerability “hot-spots” so calculated will be distributed to the research community. Ultimately, we aim to produce a tool that can aid clinicians to identify patients at risk of developing a titin-based heart condition at early disease stages, where intervention is still possible.

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Coordinador

UNIVERSITAT KONSTANZ
Aportación neta de la UEn
€ 171 460,80
Dirección
UNIVERSITATSSTRASSE 10
78464 Konstanz
Alemania

Ver en el mapa

Región
Baden-Württemberg Freiburg Konstanz
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 171 460,80