HEИндивидуална стипендия2023–2025

HYPOXIA · Highlighting Novel Mechanisms SwaYing ErythroPOietin EXpressIon and RegulAtion

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

Период: 2023-02-03 → 2025-06-02
Финансиране от ЕС: 225 904 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите за регулиране на хормона еритропоетин се изследват чрез анализ на мутации при пациенти с наследствена еритроцитоза. Това помага за по-доброто разбиране на редките заболявания на кръвта и разработването на нови терапевтични методи.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Highlighting Novel Mechanisms SwaYing ErythroPOietin EXpressIon and RegulAtion

Context and Motivation The HYPOXIA project is rooted in a critical medical and scientific challenge: the incomplete understanding of erythropoietin (EPO) regulation and function in human health and disease. EPO is a central hormone regulating red blood cell production, and its dysregulation is implicated in conditions such as hereditary erythrocytosis (HE) and various hypoxia-related disorders. Despite its clinical relevance, the complexity of EPO gene structure and its non-coding regulatory elements remains poorly understood. Recent discoveries by the host lab and European collaborators identified novel gain-of-function (GOF) mutations in the non-coding regions of the EPO gene in patients with HE. These mutations appear to create a more active EPO with normal serum levels but abnormally high biological activity—suggesting a new class of naturally occurring, high-performance EPO proteins with broad therapeutic potential. This opens an entirely new frontier for investigating EPO biology, therapeutic applications, and the molecular basis of disease. Strategic and Political Relevance The HYPOXIA project aligns with key EU strategic goals, particularly within the Horizon Europe framework, targeting rare diseases, personalized medicine, and responsible research and innovation (RRI). It supports the EU's ambition to develop novel, safe, and affordable therapeutic options by using cutting-edge genomic technologies, high-throughput functional assays, and advanced cellular modeling. Moreover, it responds to societal needs by seeking to improve diagnosis, treatment, and understanding of rare erythropoietic disorders, many of which are under-researched and underserved. Overall Objectives The project is designed to: 1. Dissect the regulatory and splicing mechanisms governing EPO expression, especially those affected by pathogenic mutations. 2. Develop a human disease model using hiPSC-derived EPO-producing cells that closely mimic patient pathophysiology. 3. Characterize the novel EPO at molecular and functional levels, with the goal of understanding their pathological roles and therapeutic potential.

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

Цел на проекта

Cellular adaptation to oxygen deficiency (hypoxia) is a complex biological process. Germline mutations occurring in the hypoxia genes pathway provided major information to dissect the molecular mechanisms regulating this pathway. The objective of HYPOXIA project is to elucidate the molecular and regulatory mechanisms governing erythropoietin (EPO) gene expression, a major actor of the hypoxia pathway. The originality of HYPOXIA lies in identifying naturally occurring germline EPO mutations in patients with hereditary erythrocytosis presenting excess red blood cells production. Recently, the host laboratory and European collaborators have identified intriguing genetic variants located in non-coding sequences of EPO in six families with erythrocytosis. Remarkably, all families exhibited normal circulating EPO levels, suggesting gain-of-function potentials of the new EPO. EPO is the hormone that regulates daily red blood cells production and its regulation greatly depends on the developmental stage, cellular type, and oxygen concentration. Given the complexity in EPO regulation, HYPOXIA aims at deciphering the expression and splicing mechanism of the newly identified EPO. I will use an innovative cellular disease model based on differentiating human induced pluripotent stem cells (hiPSCs) into different EPO-producing cells (neural crest cells and hepatocytes). The wild-type, edited, and mutant cells will then be studied using Next Generation Sequencing approaches (RNAseq and ATACseq). Besides its erythropoietic role, studies have highlighted various pleiotropic effects of EPO such as its protective role in ischemic injury and wound healing and regulation of metabolic homeostasis including gender-specific EPO response. Thus, HYPOXIA cellular model may lead to the development of new therapeutics or treatments for erythrocytosis, anemia, and other EPO-related disorders. The newly identified EPO isoforms might render this cytokine a promising game changer in human health.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция