H2020Индивидуална стипендия2021–2023

CODICES · Exploring new genetic causes and pathological mechanisms of epileptic focal cortical dysplasia

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

Период: 2021-09-01 → 2023-08-31
Финансиране от ЕС: 196 708 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните причини за фокалната кортикална дисплазия, като мутациите в mTOR пътеката, които нарушават структурата на мозъчната кора, се анализират чрез лабораторни модели. Разбирането на тези механизми е необходимо за разработването на по-ефективни и по-малко инвазивни методи за лечение на епилепсията.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Exploring new genetic causes and pathological mechanisms of epileptic focal cortical dysplasia

Focal cortical dysplasia (FCD) is a rare, genetic, non-syndromic developmental malformation of the cerebral cortex that accounts for 5-10% of patients with focal epilepsy, and that represents the main cause of pharmaco-resistant epilepsy. FCD affects mainly children and young adults, and nowadays the only treatment available is invasive surgical resection of the brain epileptogenic zone, which is effective in only 62% of cases. Thus, a better understanding of the disorder is urgent in order to point towards strategies that would allow to generate new, more effective and less invasive treatments. Among FCD subtypes, FCD type 2 (FCD2) is characterized at the histopathological level by an abnormal structure of the cortex in the area affected by the disorder, where the characteristic six-layer structure appears disrupted. Abnormally large (cytomegalic) cells are also a classic hallmark of FCD2. Around 60% of FCD2 cases are due to inherited germline and/or de novo somatic mutations in genes regulating the mechanistic target of rapamycin (mTOR) pathway, which regulates cell growth, metabolism and proliferation. These mutations always cause a hyperactivation of the mTOR pathway that is thought to be associated with the aforementioned hallmarks of the disorder. Together with its focal nature, the role of somatic mutations in causing the disorder has recently defined FCD as a mosaic disorder of the brain. Despite these findings, a clear understanding of the consequences of mTOR pathway mutations, and especially mosaic mutations, in the development of the cerebral cortex and the insurgence of the disorder is still missing. This project addressed the genetic, cellular and molecular mechanisms underlying the pathophysiology of FCD2 by modeling the disorder in vitro using 3-dimensional culture systems called cortical organoids that are generated from patient-derived human induced pluripotent stem cells (hiPSCs). This system has the advantage of reproducing developmental features specific to humans, and thus overcomes existing limitations encountered in mouse models, where the disorder is only partially reproducible.

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

Цел на проекта

Focal cortical dysplasia (FCD) is a rare, genetic, non-syndromic developmental malformation of the cerebral cortex that accounts for 5-10% of patients with focal epilepsy. FCD represents the main cause of pharmacologically intractable epilepsy, the only treatment available consisting of invasive surgical resection of the epileptogenic zone, which results effective in only 62% of patients. Thus, a better understanding of this disorder is necessary to develop more effective and less invasive treatments. FCD type 2 (FCD2) is an mTORopathy caused by genetic mutations that cause hyperactivation of the mTOR pathway, leading to abnormal cell size (cytomegalic dysmorphic neurons and balloon cells) and disruption of the structure of the cortex. Recently, the supervisor S. Baulac and others have partially explained the focal nature of the disorder by identifying post-zygotic somatic (mosaic) mutations in a percentage of cells that correlates with the size of the lesion. Despite this, the underling genetics remains unknown for ~40% of FCD2 patients. My first objective is to perform deep whole-exome sequencing of a cohort of 60 unsolved FCD2 cases to explore alternative pathways and find possibly pathogenic variants, focusing on those with an established link with mTOR pathway and/or neurodevelopment. Abnormal cells found in FCD2 lesions have been hypothesized as the source of the epileptogenic activity. However, the developmental origins of these cells are still unclear, and there is a need to find clear biomarkers that can clarify the link between mTOR hyperactivation and neuronal hyperexcitability. This project aims to clarify these aspects by applying my expertise in single cell genomics and S. Baulac’s expertise in functional studies and disease modelling in human brain organoids. The MSCA IF will allow me to reintegrate in Europe after a 4-years+ postdoc in the US and complete my training with the objective of applying to set up my own lab at the end of the two years.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE · ParisКоординаторФранция