H2020Индивидуална стипендия2019–2021

R-FunSel · In vivo functional screening via CRISPR-Cas9 to systematically identify cardiomyocyte receptors as targets for the innovative therapies for myocardial infarction and heart failure

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-04-01 → 2021-03-31
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

Рецепторите на сърдечните клетки се анализират чрез генетичното редактиране CRISPR-Cas9 при мишки, за да се установи кои от тях помагат или пречат на оцеляването на клетките след инфаркт. Това помага за откриването на нови цели за създаване на биологични лекарства срещу сърдечната недостатъчност.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

In vivo functional screening via CRISPR-Cas9 to systematically identify cardiomyocyte receptors as targets for the innovative therapies for myocardial infarction and heart failure

There is an urgent need to develop new therapies for myocardial infarction to prevent cardiomyocyte loss, improve cardiac dysfunction and prevent eventual heart failure. All the currently available therapies are based on pato-physiological concepts developed in the mid-90’s or earlier and all drugs are small molecules. Compared to other fields in which biological drugs (in particular, monoclonal antibodies and recombinant proteins) have literally changed patients’ management (e.g., cancer and rheumatic disorders), not a single biological drug exists for any cardiac disease. A class of particularly appealing drugs are those targeting cell surface receptors expressed in cardiomyocytes. However, scanty information is currently available on targetable/druggable receptors in these cells, and the presence of receptors themselves is, in most cases, only inferred from RNA expression studies, with limited insights into their biological role. The R-FunSel project was aimed to identify novel therapeutic targets for myocardial infarction, the leading cause of heart failure. R-FunSel takes advantage of the CRISPR/Cas9 genome editing technology to perform in vivo systematic screenings of cardiomyocyte receptors. For this purpose, the project takes advantage of a mouse model of myocardial infarction to identify receptors necessary for cardiomyocyte survival as well as receptor playing a negative role. R-FunSel offers an unbiased way to shed light on the mechanisms regulating the outcome of myocardial infarction, contributing to the translation of basic research into novel therapeutic targets.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Myocardial Infarction (MI) is the leading cause of heart failure, which represents a major medical, social and economic burden worldwide. There is a desperate need for new therapies for these conditions. Here we propose a new approach for the in vivo, unbiased and systematic identification of receptors involved in MI, which might become targets for innovative therapeutics. The method we developed, named Reverse Functional Selection (R-FunSel) takes advantage of the CRISPR/Cas9 genome editing technology and is based on the intracardiac screening of a library of single-guide (sg) RNAs in Cas9 transgenic mice upon gene delivery using the highly cardiotropic adeno-associated virus serotype 9 (AAV9). First, we will construct an arrayed library of sgRNAs, individually cloned into AAV9 vectors, driving CRISPR/Cas9 towards each of the receptor genes expressed by cardiomyocytes. Second, we will package pools of this library and transduce the mouse heart, at a multiplicity by which each vector enters a different cell. Then, MI will be applied as a selective stimulus and, after a few weeks, vector inserts will be recovered from the viable tissue and their frequency measured by Next Generation Sequencing. R-FunSel is based on Darwinian selection of cardiomyocyte survival, thus sgRNAs that will be lost are likely to target cardioprotective genes while those that are enriched code for detrimental factors. The choice to develop R-FunSel for the systematic screening of cardiomyocyte receptors will allow identification of novel druggable targets for the development of therapeutics, either in the form of molecules activating the protective receptors or inhibiting them or their ligands. R-FunSel is based on solid technologies that support the feasibility and power of the in vivo screening approach. Compared to biochemical or phenotypic studies, screening in vivo directly for function is a novel strategy to move basic research into translational medicine at a quick pace.

Оригинален текст от CORDIS (на английски).

Участници

KING'S COLLEGE LONDON · LondonКоординаторОбединеното кралство