Doctoral students

Thesis project abstract:

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder affecting 8-13% of women of childbearing age worldwide. In addition to representing one of the main causes of infertility in women, this pathology can alter menstrual cycles and cause acne, hyperpilosity, hair loss and weight gain, as well as increasing susceptibility to developing other health problems (diabetes, hypertension, hypercholesterolemia, heart disease, cancer).

Endocrine disruptors (EDs) are substances, natural or synthetic, that can interfere with hormone production and action in the body. New studies suggest that exposure to EPs may be a causal factor in PCOS.

The aims of Lucille Berthet’s thesis project are to identify the main EDs present in the follicular fluid ¹ of PCOS patients, compared with non-PCOS patients, using a non-targeted mass spectrometry approach. The role of the main EDs identified will then be investigated in ovarian follicle cells, the granulosa cells. Effects on cell viability, proliferation and steroidogenesis ² will be assessed individually, as well as in mixtures. This analysis will be carried out in vitro, on patient cells, as well as in vivo, in a rat model of spontaneously developing PCOS. This model will enable in-depth analysis of the effects of dietary exposure to EDs during gestation on female offspring, as well as on the production and quality of their gametes in adulthood.

The ambition of this research is to open up new perspectives in the management of PCOS patients.

¹ Follicular fluid: a liquid rich in growth factors, nutrients, metabolites and hormones, present in the ovarian follicles in which the ovocytes develop.

² Steroidogenesis: the process of synthesizing steroid hormones, which are involved in functions such as growth, metabolism and reproduction.

Thesis supervision: Joëlle Dupont – INRAE, CNRS, Université de Tours

Thesis project abstract:

Infertility is a major public health issue that can have a profound impact on the lives of those affected. Several studies indicate that a functional, well-synchronized biological clock is necessary for the proper functioning of female reproductive cycles and fertility. However, in industrialized societies, around 15% of women work staggered hours.

The aim of Élisa Nied’s thesis project is to study how shift work affects female reproductive health.

Using female mice as an animal model, this project tests the hypothesis that disruption of the light/dark cycle, as experienced by women working shifts, alters the function of the hypothalamic-pituitary-ovarian axis ^[1], which could lead to reduced fertility and impact on offspring development. This project also aims to develop different chronotherapeutic protocols ^[2] promoting resynchronization of the reproductive axis in female mice chronically exposed to time shifts, in order to improve their fertility.

^[1] Hypothalamic-pituitary-ovarian axis: pathway linking the hypothalamus, pituitary and ovaries. The hypothalamus releases a hormone to the pituitary which induces the latter to synthesize LH and FSH, hormones which act on the ovaries. The ovaries produce other hormones targeting, among others, the hypothalamus and pituitary gland.

^[2] Chronotherapy: approach aimed at administering a drug treatment at the best time of day or night, depending on its target and the biological rhythms associated with it. To find out more, read the Inserm article “À la bonne heure – C’est quoi la chronothérapie?” (in French only).

Thesis supervision: Valérie Simonneaux – CNRS

Thesis project abstract:

The development of an embryo begins with the activation of its genome and the acquisition of pluripotency, the property enabling cells to differentiate into other cell types and thus generate a complete organism.

These key events require epigenetic regulation of gene expression, i.e. the reorganization of chromatin, formed by DNA and its architect proteins called histones. However, the precise mechanisms by which histone marks ¹ are interpreted and govern these processes after fertilization remain poorly understood.

Hugo Saavedra’s thesis project focuses on the role of a protein called SPIN1, a chromatin reader abundantly supplied to the embryo by the ovocyte at the time of fertilization. SPIN1 is a protein capable of recognizing various histone marks. The working hypothesis of this project is that SPIN1 would serve as a versatile platform, like a conductor of an orchestra, to coordinate gene expression via various chromatin pathways in the ovocyte and early embryo. These actions would then have crucial effects on the progression of embryonic development and, consequently, embryo viability and reproductive success.

¹ Histone marks: modifications of histones (mainly by acetylation, methylation, phosphorylation or ubiquitination) enabling the recruitment of proteins capable of modifying chromatin structure.

Thesis supervision: Deborah Bourc’his – Institut Curie, Inserm

Thesis project abstract:

With 15 to 25% of couples of childbearing age affected, infertility represents a real public health problem. While advances such as medically assisted reproduction (MAP) bring hope, questions persist as to who can access these treatments. Research in the social sciences and humanities points out that marginalized populations, such as incarcerated women, face additional obstacles to reproductive health.
Since the January 18, 1994 law on public health and social protection, the health of people in prison has been overseen by the Ministry of Health. By law, this means that access to infertility treatments, such as MAP, must be the same in prison as in the community. However, the situation of imprisonment calls this ideal into question, since access to care involves a greater number of players (hospital, wardens, prison administration, gendarmerie, etc.). So, despite a legal framework guaranteeing equal access to healthcare, many obstacles stand in the way of access in detention.

Cécilia Travagli-Chanal’s thesis project aims to explore these obstacles, looking at both the rights of incarcerated people and institutional attitudes. The aim of this research is to study public policies on reproductive infertility and their effective transcription within the prison environment. Using qualitative methods, the study seeks to shed light on this under-explored issue, and to enrich and illuminate ethical debates on reproductive autonomy and social justice.

Thesis supervision: Nathalie Le Bouteillec – Ined, Université de Picardie Jules Vernes

Thesis project abstract:

Carney complex (CNC) is a rare genetic disorder caused by a mutation that induces increased PKA protein activity, leading to ovarian failure associated with poorly understood functional and tissue alterations. More broadly, ovarian failure, which affects 3.7% of women under the age of 40, causes infertility, and its genetic origin is identified in only 24% of cases.

Using ovaries from mouse models reproducing CNC mutations, and integrating bioinformatics and imaging analysis tools, Florian Chaleil’s work has demonstrated the involvement of PKA activity in controlling the programs that guarantee postnatal ovarian identity, and deciphered the associated molecular mechanisms. It has also highlighted the central role of an epigenetic mark, called SUMOylation, in ovarian function, and identified the mechanisms by which PKA controls this mark.

Florian’s project now aims to build on these results by developing new mouse genetic models, extending the analysis to human CNC ovarian biopsies, and fully exploiting bioinformatics data.

This work will lead to fundamental advances and new discoveries on the tissue and functional plasticity of the ovary necessary for reproductive function, as well as on the genetic causes of ovarian failure in women.

Thesis supervision: Anne-Marie Lefrançois Martinez – iGREeD, CNRS, Inserm, Université Clermont Auvergne

Thesis project abstract:

DNA is not naked: it is organized into nucleosomes, structures formed by histones that ensure the proper packaging of the genome and, consequently, its proper functioning during gene expression, as well as DNA repair, replication, and division. Certain histones, known as “variants,” have specialized roles, some of which are still poorly understood.

During spermatogenesis, a unique transition takes place: histones are replaced by non-histone proteins, protamines, preceded by profound chromatin rearrangements, often involving histone variants.

Emmanuel Gonzalez Sqalli’s thesis project explores these dynamics in the emerging model Gryllus bimaculatus, the Provençal cricket, focusing on the role of histone variants. Unlike more broadly used models as Drosophila melanogaster, the cricket retains several histone variants considered specific to vertebrates, such as macroH2A, which is at the heart of this study. This protein, involved in chromatin compaction, transcriptional repression, and DNA repair, remains poorly characterized.

The cricket offers a simpler context for its study, with a single macroH2A protein (compared to three in vertebrates). The results of the study reveal dynamic expression of macroH2A during meiosis and a marked decrease in fertility in male and female mutants, highlighting its key role in reproduction.

Thesis supervision: Benjamin Loppin – ENS de Lyon, CNRS

Thesis project abstract:

The peripheral nervous system is a vast network of nerves that connects the brain to almost every organ in the body, including the female reproductive system. These nerves can change their structure and function in response to various external and internal signals, such as hormones. In the uterus, this means that innervation changes dynamically throughout the menstrual cycle and pregnancy. For example, during pregnancy, the number of nerves in the muscle layer of the uterus decreases, which may help keep the uterus relaxed until the time of delivery.

However, the inner lining of the uterus, called the endometrium, has fewer nerves, making it difficult to study using standard methods. Using advanced imaging techniques and female mice as a model, Kato Herman’s thesis project will create a detailed 3D atlas of uterine nerve networks throughout the reproductive cycle and after embryo implantation.

The working hypothesis of this project is that the nerves in the endometrium communicate with the uterine glands. Disruptions in this communication between nerves and glands could affect the uterus’s ability to support pregnancy and may help explain reproductive health problems such as infertility or endometriosis, a painful and underdiagnosed condition that affects about one in ten women.

Thesis supervision: Fanny Mann – CNRS, and Pascale Durbec – CNRS

Thesis project abstract:

Genetically, men and women differ in their sex chromosome pairs: XX for women and XY for men. Most genes on the X chromosome are therefore present in two copies in women, but only one in men. To avoid an imbalance in gene expression, one of the two X chromosomes is “silenced” in each cell in women. This process, called “X chromosome inactivation,” begins early in embryonic development and is maintained throughout life.

In mice, this mechanism has been shown to be essential for the proper development and survival of female embryos. However, in humans, the role of this inactivation in the early stages of life is not yet known.

Margot Hully’s thesis project aims to understand the importance of X chromosome inactivation for the development of human female embryos and, therefore, for reproductive success. Using advanced genetic tools and 3D cell models that mimic human embryogenesis, this project will study the consequences of a disruption in this inactivation on two key points:

1. the efficiency of embryo implantation in the uterus, using an artificial model developed in the laboratory
2. the formation of the first cell types necessary for the correct development of the embryo

Thesis supervision: Claire Rougeulle – Institut Curie, CNRS, Sorbonne Université,Université Paris-Cité, and Charbel Alfeghaly – Institut Curie, CNRS, Sorbonne Université, Université Paris-Cité 

Thesis project abstract:

Meiosis is the process by which a cell divides twice in succession without duplicating its genetic material to produce gametes: oocytes or spermatozoa.

Improper separation of chromosomes between cells during these divisions leads to aneuploidy, an abnormal number of chromosomes in the gamete. After fertilization, this abnormality can lead to spontaneous abortions or developmental disorders.

In humans, the rate of oocyte aneuploidy increases with maternal age, with up to 60% of gametes affected in women over 40.

The kinetochore is the protein structure that links the chromosomes to the segregation machinery during division, allowing the correct ploidy[1] to be maintained. Léo Lenhardt’s project aims to describe a new kinetochore assembly pathway discovered in the oocyte meiosis of the nematode[2] C. elegans.

This project will consist of defining the roles and molecular mechanisms of the already known actors and identifying the missing elements, with the aim of establishing an overall picture of this alternative pathway.

Several proteins in this alternative pathway are also present in the kinetochore of other species, including humans, indicating that the pathway may also be conserved. This project proposes to test this possibility by studying human oocytes.

[1] Number of chromosome sets present in a cell.

[2] Roundworms.

Thesis supervision: Julien Dumont – CNRS

Thesis project abstract:

Today, approximately 7% of men worldwide are infertile, and this trend is increasing. This can be the result of genetic mutations, disease, or lifestyle factors (such as smoking). Infertility is often due to a lack of sperm, caused by the unexpected cessation of spermatogenesis. This is the process of cell differentiation whereby stem spermatogonia undergo chromosome mixing followed by two cell divisions, called “meiotic divisions,” to produce sperm. When a step in this process does not occur correctly, infertility occurs. At the molecular level, the programmed and selective degradation of messenger RNA (mRNA) appears to influence the proper functioning of spermatogenesis.

Giulia Perrotta’s thesis project aims to decipher the role, during spermatogenesis, of the CNOT11 protein that is a member of a multimolecular complex involved in mRNA degradation:. Using genetic approaches in mice, Giulia invalidated the gene encoding CNOT11 in spermatogonia and discovered that this causes infertility due to a stop in spermatogenesis at the end of the first meiotic division. Her work shows that CNOT11 controls the expression of several key players specific to this division and that the molecular mechanism involved does not involve mRNA degradation, as initially expected.

The project now aims to understand the molecular mechanism(s) by which CNOT11 acts on spermatogenesis. Although this is fundamental research, the project will help to understand the molecular basis of spermatogenesis and, consequently, the causes of male infertility.

Thesis supervision: Norbert Ghyselinck – IGBMC, CNRS, Inserm

Thesis project abstract:

Endometriosis is a chronic inflammatory gynecological disease, affecting around one in ten women. It is characterized by the implantation of cells resembling those of the inner layer of the uterus, outside the uterus, usually in the peritoneal cavity. Endometriosis leads to inflammatory reactions, with the formation of scar tissue and adhesions between neighbouring organs, as well as severe pain. Endometriosis is sometimes associated with infertility, and is one of its main causes.

The origins of this disease appear to be multifactorial, stemming from a complex interaction between genetics and environment. One gene in particular has been highlighted by a team at the Institut Cochin as a potential major player in familial cases of endometriosis.

Nastia Colin-Laignelet’s thesis project aims to study this gene in detail, in order to understand its functions and how its variability could impact biological mechanisms linked to endometriosis. An understanding of the mechanisms involved and their dysfunctions will enable action to be taken at both diagnostic and curative levels.

Thesis supervision: Daniel Vaiman – Institut Cochin, and Catherine Patrat – Institut Cochin

Thesis project abstract:

Endometriosis is a common multifactorial condition triggered by the presence of endometrium-like tissue outside the uterus. To date, there is no treatment that can permanently eliminate lesions and prevent recurrence.

Immune system cells play a key role in the disease, and the specialized environment surrounding the lesions impacts the function of these cells. In endometriosis, the immune response that develops does not allow for the elimination of this endometrial tissue. On the contrary, this particular environment seems to contribute to the development of endometriosis lesions.

A team from the Toulouse Institute for Infectious and Inflammatory Diseases has identified molecular targets, expressed by the lesions and surrounding immune cells, that prevent an effective immune response from developing. Inhibitors of these targets exist and are currently used in the fight against cancer.

The EndoTherapy project, led by Élisa Dalbard, aims at proposing a new therapeutic strategy based on blocking these molecules in order to induce the restoration of a proper immune response. This would not only eliminate existing lesions but also prevent new ones from forming.

Thesis supervision: Julie Tabiasco – Inserm

Thesis project abstract:

Endometriosis is an inflammatory disease associated with chronic pain, infertility, and an increased risk of ovarian cancers, particularly clear cell and endometrial subtypes. Endometriosis is also a fibrotic disease[1], meaning that fibroblasts play a key role in the pathophysiology of the disease. However, their heterogeneity and the role of stromal diversity[2] in the disease are still poorly understood.

Valentine Fournier’s thesis project will draw on knowledge acquired in the field of cancer and fibrotic diseases to better understand the cellular composition of endometriosis lesions, with a particular focus on fibroblasts and their interactions with immune and epithelial cells.

In close collaboration with clinicians, the project aims to (1) define the cellular heterogeneity and spatial organization of endometriosis lesions; (2) define the associations between specific cellular niches[3] and the clinical outcomes of patients with endometriosis; and (3) determine and validate the cellular and molecular interactions responsible for endometriosis features and cancer development.

[1] Fibrotic disease: excessive fibrosis that hardens tissues or organs and may impair their function

[2] Stromal diversity: the different cell populations present in this microenvironnement

[3] Cellular niches: cell populations clustered together due to their spatial proximity (characterized by spatial transcriptomics)

Thesis supervision: Fatima Mechta-Grigoriou – Institut Curie, Inserm, CNRS

Thesis project abstract:

Endometriosis is a common gynecological condition in which tissue similar to that lining the uterus grows elsewhere in the body, causing pain and complications. The causes of this condition are not yet well understood.

Recent research has revealed that certain changes in the way DNA is organized within cells could impact gene expression and promote the aggressive form of the disease. The metabolism of our cells, which depends in part on our diet, plays an important role in influencing the mechanisms that control this gene activity.

In this context, Lisa Germain’s project proposes to test the impact of cell metabolism on the regulation of genes responsible for the progression of endometriosis. This study could open up new avenues for better controlling the symptoms of the disease through diet, thereby improving patients’ lives.

Thesis supervision: Guillermo Orsi – IAB Grenoble, Inserm, CNRS, Université Grenoble Alpes

Thesis project abstract:

Endometriosis is a chronic gynecological condition affecting 5 to 10% of women of childbearing age. It is characterized by the presence of endometrium-like tissue outside the uterus, causing menstrual pain, digestive and/or urinary problems, and fertility issues. Diagnosis is based on medical imaging (MRI, ultrasound), but these techniques cannot detect certain lesions, such as those invisible to the naked eye, atypical, deep, or affecting multiple organs.

The EndoSurgAI thesis project, led by Astrid Vidal in partnership with the EnCoV laboratory and the start-up SurgAR, aims to develop and validate, both technologically and clinically, innovative software combining artificial intelligence and augmented reality to assist surgeons. This software will automatically analyze surgical images, particularly those from laparoscopy¹, using a neural network². It will enable the precise identification of organs and lesions, improving the accuracy of procedures and patient care.

¹ Minimally invasive surgical technique.

² Artificial intelligence model capable of learning to recognize shapes in data such as images.

Thesis supervision: Nicolas Bourdel – Université Clermont Auvergne, and Adrien Bartoli – CHU Clermont-Ferrand