The heart is made up of four valves, allowing unidirectional blood flow. Valve leaflets are composed of valvular endothelial cells on their surface and valvular interstitial cells within their structure. Valve diseases (valvulopathies) affect all four heart valves, but more frequently the aortic and mitral valves. Approximately 2% of the adult population suffers from valvular disease, and this frequency increases with age, reaching around 13% in people over 75.

Cellular models enabling us to mimic these pathologies are still limited. There is therefore a need to develop a model for studying valve pathophysiology using patient-derived human induced pluripotent stem cells (hiPSCs). In recent years, several protocols for differentiating hiPSCs into valve cells have been established. The aim of my internship was to validate one of these protocols for obtaining valve cells and to use it with iPSCs derived from a patient with mitral valve prolapse. My results enabled me to validate a protocol and show morphological and gene expression differences in the patient-derived cells.

In the long term, this project will provide a better understanding of the impact of the variants identified in patients with valve disease.

• Host laboratory: MMG, eq. Networks and Systems Biology, dir. A. Baudot

I did my Master 2 bioinformatics internship at the Marseille Medical Genetics Center (MMG) in the Systems Biomedicine team. During this internship, we focused on diseases associated with a premature aging phenotype. These are rare genetic diseases that mimic certain aspects of physiological aging, but at an early age. They are characterized by clinical and genetic heterogeneity, making them complex to study. Here, we have analyzed these pathologies of premature aging through biological interaction networks. A biological network contains nodes representing biological molecules, and edges representing their interactions. By analyzing the genes mutated in premature aging diseases within the network, we can learn more about the biological processes disrupted in these diseases.

In a biological network, we detected gene communities associated with 67 premature aging diseases. We then compared the diseases according to their gene communities, in order to determine groups of diseases sharing common biological causes. We were able to highlight various molecular processes disrupted during premature aging, such as DNA repair, the cell cycle and cell-to-cell communication.

• Type of project : Collaboration (Nov. 2022)
• Project location: ImpedenCELL platform, Caen

Since 2011, cancer immunotherapies have made it possible to treat a growing number of patients with particularly aggressive cancers. Their principle is to restore the activity of the immune system to destroy cancer cells. These treatments can cause inflammation of various organs, which is usually minor. Unfortunately, in very rare cases, immunotherapy causes inflammation in heart tissue, leading to myocarditis, which is fatal in almost one in two patients. Today, the cause and mechanisms of this myocarditis remain poorly understood, and are the subject of my thesis work. As cardiac biopsies are difficult to perform and very risky for the patient, I use a genetically modified cell model (hiPSC for human induced Pluripotent Stem Cells) derived from patients' blood cells.

I have perfected the differentiation of these hiPSC cells into cardiac cells to study the mechanisms associated with myocarditis. To do this, I am comparing the results obtained in cells from patients treated for melanoma, who developed myocarditis after immunotherapy, with cells from patients who did not develop myocarditis. The results I obtained showed that the heart cells of patients who developed myocarditis had a different inflammatory response to the heart cells of patients who did not. Thanks to the support of the Institut MarMaRa, I was able to move to Caen, on the ImpedanCELL platform, and benefit from their equipment and experience in order to study the cell death mechanisms associated with inflammation in cardiac cells. This work is currently being analyzed and should soon give rise to a publication.

• Thesis title: Identification of pathophysiological mechanisms in congenital cardio-neurocutaneous syndromes
• Type of project: Dissemination (poster)
• Event : New Frontiers in Developmental Biology - Celebrating the Diversity of Life (nov. 2022)

Developmental diseases affecting the skin, the nervous system or the heart have a significant impact on the quality of life and fate of those affected, and I am seeking to identify common biological causes associated with the development of these different diseases. The MAP-K signaling pathway is a set of signals in cells that regulates many different processes, such as cell proliferation or differentiation. Alterations in this pathway, which appear during embryo Training, are responsible for a number of developmental syndromes with very different visible characteristics known as "RASopathies".

Congenital melanocytic nevus is an RASopathy that occurs after a mutation in the MAP-K pathway specifically in melanocytic progenitors, and presents with a spectrum of severity ranging from small, isolated lesions in the skin, to giant, often multiple lesions. I demonstrated the existence of biological differences in patients with severe forms (with increased susceptibility to cancer), providing a new parameter for early diagnosis.

We hypothesized that alterations in the MAP-K pathway could disrupt the development of other tissues. To this end, I have characterized mouse models with disruption of the MAP-K pathway specifically in the peripheral nervous system or heart. My results demonstrate the development of degenerative peripheral neuropathies or severe cardiac defects. Characterization of these models will enable me to improve our understanding of the specific physiological and pathological mechanisms involved in the development of neuromuscular diseases or heart defects.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Nam cursus at dolor in gravida. Integer accumsan vitae urna eget maximus. Duis at lectus id nulla eleifend pulvinar. Cras nulla ligula, facilisis semper felis nec, facilisis tempus enim. Nunc pulvinar mattis velit non pretium. Sed sed metus at sem pharetra condimentum sit amet sed turpis. Aenean nisl orci, imperdiet eu mauris in, interdum dignissim libero. Vivamus mattis vel quam eu congue.

Donec ac arcu ut nulla congue

dictum vitae et magna. Sed maximus sollicitudin condimentum. Praesent ligula lacus, blandit eget varius sit amet, mattis eu elit. Ut a felis id tortor viverra dapibus. Curabitur consectetur gravida fermentum. Duis ut malesuada nisl, eget congue nibh. Duis nunc nibh, feugiat semper ante vestibulum, suscipit iaculis lorem. Duis quis nulla aliquam, pharetra mauris sit amet, feugiat sapien. Phasellus dictum volutpat risus. Donec consectetur leo eget sagittis blandit. Phasellus et molestie est. Cras luctus ornare eros, ut tincidunt elit tincidunt ut. Vivamus eleifend est purus, id cursus risus pretium a. Praesent eget lorem vitae nunc accumsan dignissim sed in ante. Nam pharetra enim diam, ac dictum augue tincidunt quis.

Nunc in quam vehicula, mattis nibh nec, elementum odio. In convallis ante ac facilisis cursus. Praesent dapibus, nisi sed elementum mollis, nibh tortor euismod turpis, eget interdum dui sapien vitae libero. Phasellus in metus eros. Vestibulum quis orci suscipit tortor lobortis sollicitudin. Aenean erat lacus, pulvinar nec odio vitae, volutpat mollis ipsum. Phasellus lacinia magna a risus consequat tristique. Mauris a accumsan purus, ut congue metus. Nam non libero quis augue imperdiet lobortis venenatis in urna. Vestibulum eu justo pellentesque, aliquam augue nec, ullamcorper urna. In hac habitasse platea dictumst.