Project description
Mechanistic insight into PIK3CA-related overgrowth spectrum
PIK3CA-related overgrowth spectrum (PROS) encompasses disorders associated with overgrowth of certain parts of the body as well as vascular lesions. PROS is caused by activating mutations in the PIK3CA gene in somatic cells, and patients undergo extensive surgery, with a high risk of disease recurrence. The EU-funded PROS-VARIANT project aims to understand the molecular mechanisms underlying PROS development. More specifically, researchers will determine the timing, the cell type and the PIK3CA variant that contribute to PROS severity. The molecular evidence will be validated in preclinical models and will fuel future research towards new treatments.
Objective
PIK3CA-related overgrowth spectrum (PROS) is a group of rare congenital disorders that manifest as complex syndromes with overgrowth of several tissues (vasculature, adipose and muscle tissues, bones, brain and skin among others) or as localized lesions such as vascular malformations. PROS is caused by somatic activating mutations in the PIK3CA gene that arise postzigotically during embryonic development. Patients suffer dramatic functional and life-threatening complications and typically require extensive mutilating surgery, pulsed laser, and/or sclerotherapy. However, these treatment strategies are insufficient, and patients commonly experience a high risk of recurrence and progression. This is in part a reflection of poor understanding of the underlying cellular and molecular mechanism of their onset and progression. In this proposal, I aim to gain physiological and molecular insight into PROS and address fundamental biological questions concerning when (timing), where (cell linage), who (PIK3CA variant) and how (triggered mechanism) activating PIK3CA variants contribute to the development and severity of PROS. I will address the following key objectives: 1) identify the specific molecular and cellular alterations triggered by strong (H1047R) and weak (E726K) activating PIK3CA variants and 2) characterize their spatiotemporal pathogenesis in PROS using novel mice models. To this end, a combination of in vitro and in vivo approaches, using novel genetically modified mice will be implemented in order to provide new mechanistic insight into the underlying disease pathology and give rise to new preclinical models to test therapeutic treatments. Achieving these goals will strongly contribute to my training as international expert in PI3K signaling, cell biology and congenital diseases, my experimental skillset, and my development towards a well-embedded and independent researcher within European academia.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepathology
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
08916 Badalona
Spain