Congratulations to the two first CARe students to defend their thesis!

Emmanuel Gonzalez Bautista and Lea Da Costa Fernandes were the first two PhD students of the CARe Graduate School to defend their thesis.

Emmanuel’s thesis defense took place on December 5th, 2022, on the subject “Screening for abnormalities of intrinsic abilities with advancing age within the framework of the WHO ICOPE program: example of the locomotion approach”, under the supervision of Pr. Sandrine Andrieu and Philipe de Souto Barreto, from the Centre for Epidemiology and Research in Population Health – CERPOP.

Lea defended her thesis on March 21st, 2023, on Modeling the inflammatory response dynamics following tissue damage in adult mammals”, under the supervision of Pr. Beatrice Cousin of the Restore Institute, and the co-supervision of François Peres, from the National School of Engineering in Tarbes – ENIT.

We congratulate them on this achievement and wish theme every success in their future career.

Launch of CARe’s 2023 call for PhD proposals 2nd phase

The pre-selected projects in the framework of CARe’s 2023 call for PhD proposals are available here.

PhD candidates for the pre-selected projects will submit the full proposal to Claire Mendoza (claire.mendoza-berrio@univ-tlse3.fr) and Clemence Grosnit (clemence.grosnit@univ-tlse3.fr) using this template. PhD candidates must be identified and are asked to send a complete CV including references.

At this step, PhD candidates must be identified and are asked to send a complete CV. Special attention will be given to candidates coming from foreign universities or countries. In addition, it is mandatory to provide a full description of the 3-6 months internship, including a signed attestation from the hosting foreign university or from industry.

The files must be submitted as a single PDF before May 12th, 2023. Applicants will defend their proposal in early June 2023, in front of a jury representative of the CARe Graduate school, with delegates from Toulouse partner doctoral schools.The audition will consist of 12 minutes of presentation and 15 minutes of questions. The presentation and the answers to questions will be done in English.

The presentation must include, in this order, 1 title slide, 1 slide presenting the candidate. The rest of the slides are dedicated to the presentation of the project (scientific justification of the research project, strategy, methodology, feasibility and risk management), including a description of the internship abroad or in industry. The following criteria will be evaluated by the jury: discussion of a previous research experience, quality of the oral presentation and of the response to questions.

Our 2023 call for PhD proposals is open

2023 Call for PhD proposals

 

The EUR CARe PhD program is devoted to the training of students in multidisciplinary research topics, from basic science to clinical or pharmacological applications, with a focus on cancer, ageing and/or rejuvenation. PhD research projects are directed by CARe-associated research teams from academic laboratories or partner companies. The EUR CARe PhD program selection will have two phases:

Phase 1: PhD pre-proposals will be submitted to Claire Mendoza (claire.mendoza-berrio@univ-tlse3.fr) and Clemence Grosnit (clemence.grosnit@univ-tlse3.fr) using this template, before evaluation and selection by the CARe Scientific Committee. Deadline for application is February 24th, 2023. Upon acceptance, the proposers will be informed, and the proposals will be posted on-line on the EUR CARe website and social networks.

The applications must fall in the field of cancer, ageing and/or rejuvenation. In addition, multidisciplinary is mandatory and proposals must be at the interface of biology and mathematics, computer science, chemistry or physics. Examples are: chemists, physicists, computer scientists or mathematicians addressing complex biological questions by developing new molecules, tools, technologies or models to address biological questions, possibly doing some bench work, or biologists trained to advanced bioinformatics to develop new algorithms that would be later questioned/validated in experimental biological settings…

Partnerships between teams from different doctoral schools, foreign universities or industry are strongly encouraged (see scoring below). A short internship abroad (3 to 6-month) is mandatory, the nature of which should be briefly mentioned at this step. The travel and accommodation will be funded by the CARe program.

The scoring system (out of 10) is the following:

  • Scientific quality of the proposal (6 points)
  • Co-supervision (max 4 points) by teams from different doctoral schools (2 points), or with foreign university or industry (4 points).

NB: the candidates should not be formally identified at this step.

Phase 2: PhD candidates for the preselected projects will submit the full proposal to Claire Mendoza (claire.mendoza-berrio@univ-tlse3.fr) and Clemence Grosnit (clemence.grosnit@univ-tlse3.fr) using the template that will be made available on CARe’s website.

At this step, PhD candidate must be identified and are asked to send a complete CV. In addition, it is mandatory to provide a full description of the 3-6 months internship, including a signed attestation from the hosting foreign university or from industry.

The files must be submitted as a single PDF before May 12th, 2023. Applicants will defend their proposal in early June 2023, in front of a jury representative of the CARe graduate school, with delegates from Toulouse partner doctoral schools.

The audition will consist of 12 minutes of presentation and 15 minutes of questions. The presentation and the answers to questions will be done in English.

The presentation must include, in this order, 1 title slide, 1 slide presenting the candidate. The rest of the slides are dedicated to the presentation of the project (scientific justification of the research project, strategy, methodology, feasibility and risk management), including a description of the internship abroad or in industry. The following criteria will be evaluated by the jury: discussion of a previous research experience, quality of the oral presentation and of the response to questions.

PhD fellowship at the interface between Cancerology / Immunology / Vascular biology M/F

3 years full time PhD student position funded by LABEX TOUCAN: Laboratoire d’Excellence Toulouse Cancer

starting date: October 1st, 2021

is available in the Teams of Jean-Philippe GIRARD: IPBS, CNRS and University of Toulouse, France and Camille LAURENT: CRCT, Inserm and University of Toulouse

Project Title: SINGLE CELL MAPPING OF THE VASCULATURE IN AGGRESSIVE B LYMPHOMAS AND TOPOLOGICAL INTERACTIONS WITH CD8 T CELLS AND y8 T CELLS

Keywords: aggressive B lymphoma, high endothelial venule, endothelial cell, spatial transcriptomics, scRNA-seq, anti-tumor immunity)

Abstract: Immunity plays an important role in cancer control, notably with highly mutated tumours such as Diffuse Large B-cell Lymphoma (DLBCL), an aggressive (fast-growing) non-Hodgkin lymphoma that affects B cells. Indeed, CD8 T cells and γδ T cells display potent antitumour cytotoxicity and are specifically reactive to lymphomas. DLBCL often develops in the lymph nodes. High endothelial venules (HEVs) are specialized blood vessels for lymphocyte entry into lymph nodes. HEVs may thus play an important role in the recruitment of CD8 T cells and γδ T lymphocytes in DLBCL lymph nodes.

The major objective of the project is to perform single cell mapping and spatial transcriptomics (ST) to characterize the density, maturation and functional status of HEV endothelial cells (MECA-79+CD31+) and non-HEV endothelial cells (MECA-79-CD31+), and define their topological interactions with cytotoxic  γδ T cells and CD8 T cells in DLBCL patient’s biopsies. The project will greatly benefit from the expertise of:
– Jean-Philippe Girard’s team (IPBS) on HEV blood vessels, scRNASeq analyses of endothelial cells, and HEV-mediated lymphocyte recruitment in lymph nodes (Moussion and Girard, Nature 2011; Girard et al., Nat Rev Immunol 2012; Lafouresse et al., Blood 2015; Veerman et al., Cell Rep 2019), and
– Camille Laurent’s team (CRCT) on human B cell lymphomas (Laurent et al., Blood. 2020; Laurent et al., J Clin Oncol. 2017; Laurent et al., Blood. 2011), cytotoxic T cells, single cell RNA sequencing (scRNASeq, CITEseq) (Pizzolato et al., PNAS 2019; Pont et al., Nucleic Acids Res 2019) and spatial transcriptomics (transcriptomic hallmarks of all cells in a lymphoma biopsy in situ).

This study will deeply increase our knowledge about the distribution and functional status of HEV and non-HEV endothelial cells, γδ and other cytolytic T cells infiltrating human lymphomas. It may have important clinical consequences such as the identification of new predictive biomarkers, and guide T cell-based immunotherapies currently developed in Comprehensive Cancer Centers worldwide.

Requirement: Master in Cancerology, Immunology, Vascular Biology or Molecular Biology. Experience in scRNA-seq and/or bioinformatics will be a plus. We are looking for a creative and highly motivated PhD student strongly committed to research. Joint PhD supervisors: Drs Jean-Philippe Girard (IPBS) and Camille Laurent (CRCT).

Contract: 3 years full time PhD student position funded by LABEX TOUCAN (starting date: October 1st, 2021). The salary is in accordance with the French Ministry for Higher Education and Research salary scale. Social security and health benefits are included. Work context: research conducted at both IPBS and CRCT, two large Research Centers from CNRS, Inserm and University of Toulouse. All the necessary biological resources and research facilities, including state of the art technological facilities, will be available.

 

Deadline: the position will remain open until filled; only successful applicant will be contacted

How to apply: Please, send your application (in French or English, including a motivation letter, curriculum vitae, and rankings in University Licence/Master or Engineering school).

Multi-OMICs to unveil the role of lipid metabolism in the control of senescence and cellular plasticity in melanoma

How to explore physiological aging? A new framework for an in-depth explainability of machine learning models

PhD proposal

PhD supervisor : Chantal Soulé-Dupuy – IRIT, Toulouse

PhD co-supervisor  : Paul Monsarrat – Restore, Toulouse

 

Aging is an overly complex biological process, involving multiple mechanisms at different levels, from molecular to tissue scale. With the increase of life expectancy, the challenge is to predict the physiological age to reach healthy aging, namely the one’s ability to adapt and efficiently respond to stressors. The recent use of machine learning (ML) strategies may accurately model the physiological age to prevent age-related disruption. However, black boxes properties of most ML algorithms do not support the understanding of their internal decision-making mechanisms (i.e., the explainability), crucial to highlight the critical variables on the prediction.

Using a strategy based on the coalition of attributes we recently develop algorithmic solution, whose performances and prediction qualities are superior to the gold standard SHAP (Shapley Additive exPlanation) approach. We propose to consider the prediction explanations, not as a final objective, but as a new data space allowing to impulse a better interaction between the ML model and the end user. This thesis project will focus on the development of an original framework for the biomedical community to explore in depth predictions of health evolution with age using an ML model. It will allow the detection of subpopulations with specific predictive explanations, organizing them hierarchically to ensure easy exploration. As a proof of concept, we will apply this framework to physiological age (in-house database of >40,000 subjects, 200 variables), to better understand biological determinants of ageing, their interactions, putative causal chains, and underlying physio-pathological mechanisms.

Key words: aging, machine learning

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Development of biomaterial-scaffold embedded therapeutic immune cells as a local therapy for age-associated chronic wounds.

PhD proposal

PhD supervisor : Agnès Coste -RESTORE Institute- Team 2, Toulouse, France

PhD co-supervisor: Subhankar Mukhopadhyay & D.Phil – MRC: Centre for Transplantation –  King’s College London, England

 

 

Ageing and age-associated co-morbidities are major risk factors for non-healing chronic wounds. Chronic wound represent a debilitating condition that disproportionately affects millions of elderly patients with enormous societal and economic cost.

Macrophages play a critical role in the resolution of inflammation, tissue repair and wound healing. Ageing is associated with a sustained state of non-resolving inflammation (inflammaging) driven by chronically activated macrophages. Thus, defective regulation of macrophage activation is thought to be the key driver of age-associated chronic wounds. Mesenchymal stromal cells (MSCs) can regulate macrophage activation, dampens inflammation and improves wound healing.

This project will investigate whether MSC-educated regulatory macrophages can promote wound healing by limiting inflammaging. A novel cell therapy product will be developed by embedding MSCs and macrophages within a 3D biocompatible scaffold, and its efficacy in wound healing will be assessed.

The specific aims of this project are:

  • To assess the effects of different biomaterials on MSC and macrophage-mediated immunomodulation and promotion of wound healing.
  • To assess the molecular mechanisms of MSCs-macrophages interactions within the 3D-biomaterial scaffold.
  • To determine the in vivo efficacy of this new cell therapy as a treatment of chronic wound healing.

The project will allow to develop intelligent wound plasters that will constitute a major breakthrough in the topical treatment for age-associated chronic wounds. This interdisciplinary project will take place between RESTORE and CIRIMAT institutes (Toulouse) and the Department of Immunobiology, King’s College, London.

Key words: inflammation, wound healing, ageing, scaffolds

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Development of biostatistical and bioinformatics approaches to the discovery of the sex and fat depot specific adipose tissue microbiota signature in obese patients

PhD proposal

PhD supervisor : Rémy Burcelin – I2MC:  Institute of CardioMetabolic Disease, Toulouse, France

PhD co-supervisor : Sofia Forslund – MDC Max Delbruck Center for Molecular Medicine, Berlin, Germany

 

Body fat distribution is a strong determinant of health and exhibits, as a specific feature of human beings, a marked sexual dimorphism. Women have more subcutaneous adipose tissue (SAT), while men have fat predominantly distributed to the central body visceral adipose tissue (VAT). The central accumulation of fat is associated with metabolic complications that trigger a low-grade chronic inflammation. Conversely, the SAT is rather associated with very little inflammation even in obesity.

While we and others pioneered the discovery of the first molecular mechanism of gut microbiota triggering of metabolic inflammation recently, we shifted the concept of gut microbiota towards tissue microbiota and have described in rodent models and in humans the translocation of gut bacteria towards tissues establishing a metagenomic signature within adipose tissue depots. Furthermore, is was recently shown that  the gut microbiome and abdominal obesity-related disease outcomes could account for sex-specific difference.

Altogether, while it is established that adipose depots berry bacterial components and some live bacteria it now remains to establish the molecular interactions between bacterial components and the adipose depot host cells notably regarding the role of sexual and regional differences in the development of obesity.

Thesis goal: adapt and develop bioinformatics and biostatistics approaches to identify signature of the adipose microbiota to adipose tissue molecular crosstalk. The outcome will help to identify predicting and classifying biomarkers as well as mechanisms of the influence of tissue microbiota on the adipose tissue function, thereby suitable to propose potential therapeutic strategies preventing or treating the development of obesity.

Key words: adipose tissue, microbiota, obesity, bioinformatic

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Investigating the stroma heterogeneity of adipose tissue, using AI-based label free imaging : a predictive marker of frailty ?

PhD proposal

PhD supervisor : Coralie Sengenès – RESTORE – UMR1301 INSERM 1301- UMR CNRS 5070 – Univ. P. Sabatier – EFS – ENVT, Toulouse

PhD co-supervisor : Mathieu Serrurier – IRIT – UMR 5505 – Université Paul-Sabatier, Toulouse

 

Every organ is a combination of a functional compartment, the parenchyma, and a stromal compartment, the stroma, supporting the parenchymal cells of the organ. Characterizing its involvement and defining whether and how stroma evolution can be a marker of frailty and/or can be therapeutically targeted is worthy particularly in the context of aging.

Adipose Tissue (AT) is a dynamic organ, made up of a heterogeneous stroma that is poorly understood. The stroma of AT is the richest bodily reservoir of a peculiar cell type the Adipose Stromal Cells (ASCs) that exhibit high regenerative potential. AT dysfunction is thought to be a predictor of frailty and declining health span. Here, we want to investigate the age-dependent heterogeneity of the AT stroma as a predictive marker of frailty. To address this issue methods using antibody labelling are very useful but also time consuming.

Moreover, spectral overlap inherently limits the number of simultaneous labels. Based on our preliminary data, we hypothesized that microscopic images of AT where only nuclei are stained allow the characterization of stroma’s heterogeneity using deep neural networks.

On the deep learning side, this raises many interesting problems such as the handling of pseudo-3D data, the scarcity of the data, and the prediction’s explainability that can take advantage of the strong geometric properties of the nuclei.

The PhD program aims to develop an artificial intelligence (AI)-based method of nuclei stained fluorescent images of AT to investigate the stroma heterogeneity of AT during aging.

Key words: adipose tissue, fragility, AI

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The role of nuclear organization and telomere tethering in ALT and telomerase-positive cancer cells

PhD proposal

PhD Director: Kerstin Bystricky – Molecular, Cellular & Developmental biology unit: MCD- Center for Integrative Biology: CBI, Toulouse

PhD CO-SUPERVISOR: Anabelle Decottignies – Catholic University of Louvain, Brussels


The position of nuclear chromatin domains in human cells impacts genome stability and gene regulation. The nuclear envelope (NE), which defines nuclear volume boundaries, is a keyplayer in organizing nuclear architecture as nuclear lamina protein scaffold, at its inner side, associates with large chromatin domains. During postmitotic nuclear assembly, physical connections occur between the NE and about 40 to 50% of telomeres, the chromosome ends. While suggesting a novel role for telomeres in nuclear organization, the functional significanceof this anchoring remains to be unraveled.

This proposal first intends to reveal the interplay between chromosome and telomere organization during postmitotic nuclear assembly. Interactions between telomeres and NE also likely regulate heterochromatin formation/maintenance. In telomerase-negative cancer cells that undergo recombinationmediated alternative lengthening of telomeres (ALT), telomeric heterochromatin is dysregulated.

Here, we will test the hypothesis that telomere-NE interaction may be disrupted in ALT cells to facilitate unwanted recombination events between telomeric repeats. To do this, a large panel of telomerase-expressing or ALT cancer cell lines will be used to characterize telomere-NE attachment and its impact on telomere maintenance.

Live cell imaging will be employed to investigate the kinetics of events. Artificial tethering and/or depletion of proteins involved in telomere tethering will be instrumental to characterize the functional significance of this interaction.

The strength of this proposal comes from a combination of strategies (advanced microscopy,
MadID proximity labeling, modeling) and the complementary expertise of both host
laboratories (Bystricky/Crabbe lab in chromatin organization and dynamics, Decottignies in
ALT telomere maintenance in cancer).

Key words: cancer, genome organisation, modelling

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