ESR 2: Generation of a 3D in vitro model to study cardiac fibroblast contribution to myocardial fibrosis.

ESR2

Project Title: Generation of a 3D in vitro model to study cardiac fibroblast contribution to myocardial fibrosis.

Objectives: The ESR will participate together with a multidisciplinary group in the development of a 3D co-culture system to study the molecular basis of cardiac fibroblast remodelling through the fibrotic process. Surgical samples from heart failure patients, including ischemic and dilated cardiomyopathy, will be processed to obtain disease-specific fibroblasts, and cultured together with iPSC-derived cardiomyocytes reproducing either healthy or replacement and reactive interstitial fibrosis. By tuning the biomimetic hydrogel features used for cell encapsulation, the biophysical parameters of different stages of the diseases will be also integrated into the model. The biomimicry of the engineered model will be validated by analysing the expression of several biomarkers which are clinically relevant for cardiac fibrosis (COL1/COL3 ratio, CTGF, TIMPs, MMPs, FGFs, TGFb). The contribution of different biochemical and mechanosensitive pathways to the different stages of cardiac remodelling will be evaluated though classical biochemical techniques in combination of in vivo, non-destructive cell reporters.

Expected Results: The in vitro model will recapitulate the fibrogenesis progression through the fine-tuning of substrate stiffness and cell composition in order to reflect the biomechanical heterogeneity of myocardial scarring. Thanks to its ability to monitor changes in the signalling in a controlled time frame, it will make possible to discriminate their temporal activation of important biochemical pathways during the fibrogenic process, which, in turn, can potentially lead to the discovery of new therapeutic targets in each specific stage of disease.

Host: FNUSA-ICRC

Main Supervisors: Giancarlo Forte (FNUSA-ICRC), Jorge Oliver De La Cruz (FNUSA-ICRC)

Duration: 36 months

Planned Secondment: MONZINO (3 months) to receive training on cardiac phatologies modelling and mechanisms during the first year; ACCELERA (2 months) in the second year to define a pharmacological validation strategy in line with the requirements for a new in vitro model to enter the drug discovery pipeline.

Enrolment in Doctoral Degree: PhD in Medical Biology at Masaryk University, Brno (Czech Republic)

For any specific requests on this project, please get in contact with Prof. Giancarlo Forte (Giancarlo.forte@fnusa.cz)