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Interview with Dr Luca Braga, winner of the Young Investigator Award



Luca Braga (Trieste, Italy) "Administration of miR-665 modulates cardiomyocyte mechanotransduction and prevents pathological cardiac remodelling after pressure overload"

When did you obtain your PhD/BSc degree? What was this on?

I obtained my PhD in August 2017 with a thesis focused on microRNA therapeutics in cardiac hypertrophy.

What did you do after this degree?

I started to work as a postdoc in Prof. Mauro Giacca’s laboratory at the International Centre for Genetic Engineering and Biotechnology (ICGEB, Trieste component). Since 2015, I’m also heading the core facility of High Throughput Screening (HTS) of ICGEB.

Do you have any fellowships? And what are you investigating?


My research activity as PostDoc in the molecular medicine group is now mainly focused on two fields: on the one hand I’m working on the molecular mechanisms regulating cardiomyocyte proliferation and cardiac regeneration and on the other hand I’m working on the identification of novel RNA-based therapies for cardiac hypertrophy and heart failure. In parallel, as head of the HTS facility in ICGEB, I’m currently supervising more than 15 collaborative screening projects established within the ICGEB network.

Where are you working currently?

International Centre for Genetic Engineering and Biotechnology (ICGEB), Molecular medicine group and HTS-Facility.

Have you won any other awards?

  • July 2017: Winner of the “ISHR-ES poster prize Award” at the 2017 ISHR-ES conference, Hamburg (Germany);
  • September 2013: Selected among the 10 most relevant young Italian researchers and invited to the event "ITALIAX10. Future Science”. Presented by Telecom Italia and Nordesteuropa in the context of TriesteNext conference;
  • May 2013: Awarded with “Premio Città Impresa 2013 ai 1.000 Giovani Talenti delle Venezie”;
  • October 2012: Awarded by the AIRH (Associazione Italiana Ricerca Handicap) with one year travelling fellowship to visit the European partners involved in the BetaSel project;
  • October 2011: SYNBIOME and the 2011 University of Trieste iGEM team have been awarded by the iGEM’s jury with the gold medal and assessed eligible to participate at the world championship hosted at the MIT in Boston (MA, USA).

Scientific Abstract

Cardiac hypertrophy is a process of myocardial adaptation that, depending on the type and the duration of the stimulus, can evolve from a beneficial phase of compensated hypertrophy into evident dysfunction and heart failure. To identify microRNAs able to prevent cardiac hypertrophy and preserve cardiac function, we performed a high-content microscopy, high-throughput functional screening for human miRNAs able to reduce neonatal cardiomyocyte (CM) cell size using a whole-genome miRNA library.

The most effective anti-hypertrophic miRNA was hsa-miR-665, which blocks cardiac hypertrophy and preserves cardiac function in a mouse model of HFrEF (TAC, chronic LV-pressure overload) and ameliorates LV passive stiffness in a mouse model of HFpEF (AngII sub-pressor doses). Efficacy of hsa-miR-665 in preserving cardiac function in the treated animals relies on the fact that this miRNA targets three sarcomeric proteins (Enah, Fhl1 and Xirp2), which are involved in mechanotransduction, cardiomyocytes passive stiffness regulation and myofibrillar remodelling.

Over the last couple of decades, the scientific community has made significant effort to identify novel therapies for the treatment of HFpEF in both animal models and patients, also because of the growing incidence of this condition (1% increase per year [1]). Yet, all the currently available treatments are largely ineffective. Understanding the molecular mechanisms underlying this condition and developing reliable animal models are two important bottlenecks in the process of identifying new drugs and shifting them from bench to bed side [2].

Our results on hsa-miR-665 indicate that a new generation of effective treatments might be found among nucleic acid therapeutics. In particular, miRNAs can be delivered effectively to the heart in the form of either viral vectors or as naked RNA mimics; current evidence indicates feasibility of both approaches for human therapy [3].

Citations

  1. Owan, T.E., et al., Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med, 2006. 355(3): p. 251-9.
  2. Conceicao, G., et al., Animal models of heart failure with preserved ejection fraction. Neth Heart J, 2016. 24(4): p. 275-86.
  3. Lesizza, P., et al., Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction. Circ Res, 2017. 120(8): p. 1298-1304.