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iMM

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Country: Portugal
70 Projects, page 1 of 14
  • Funder: European Commission Project Code: 101003392
    Overall Budget: 159,815 EURFunder Contribution: 159,815 EUR

    Immune cells constitute a major component of the tumor microenvironment (TME) that influence several aspects of cancer progression and outcome. The host laboratory has identified two distinct γδ T-cell subsets with opposing roles in tumor progression: whereas interferon-γ (IFN-γ)-producing γδ T-cells stimulate anti-tumor responses, IL-17A-secreting γδ T-cells promote angiogenesis and tumor growth. However, the cellular and molecular factors controlling the critical balance between these antagonistic subsets remain unknown. The present proposal builds on subsequent relevant findings of the host laboratory, namely that neutrophils suppress IL-17A+ γδ T-cell proliferation, revealing an unanticipated neutrophil/γδ T-cell crosstalk in TME, and that on another side the metabolic resources may also play a critical role in γδ T-cell subsets. Based on these foundations, within the present proposal we will: a) identify TME cellular partners that determine the balance between IFN-γ+ and IL-17A+ γδ T-cells in several experimental models of cancer. b) study the metabolic pathways employed by γδ T-cell subsets and the impact of manipulating those pathways on their balance within the TME c) analyze the impact of immune crosstalk and metabolic resources on γδ T-cell subsets both at transcriptomic and epigenetic levels. Overall, this project will provide conceptual advances that will foster innovative strategies to promote anti-tumor γδ cell functions at the expense of their pro-tumoral activities.

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  • Funder: European Commission Project Code: 713612
    Overall Budget: 150,000 EURFunder Contribution: 150,000 EUR

    MUSCLEGUY represents a unique opportunity to commercialize a novel 3D in vitro system for screening and validation of drug candidates to treat muscle disorders. Although skeletal muscle disorders are relatively rare they pose a huge socioeconomic burden. Currently there is a lack of therapeutic options for the majority of patients. This is, for an important part, due to the lack of reliable, reproducible, and physiological relevant in vitro models of muscle disorders that accurately reflect the in vivo reality on which novel therapeutic strategies may be developed. We generated a novel 3D in vitro system of highly matured myofibers, the relevant functional unit of the muscle affected in most muscle disorders and used it to identify novel therapeutic targets of muscle disorders. During MUSCLEGUY, we will further technically optimise our in vitro system to generate human relevant disease models for muscle disorder. Such systems can be used for drug screening and validation. In addition, we will further investigate the commercial feasibility of our product by conducting an elaborate market analysis and establishing a strong IP portfolio. The ultimate aim of MUSCLEGUY is to develop a business plan to convince the relevant stakeholders. Our novel 3D in vitro system for muscle disorder has the potential to meet the requirements for pharmaceutical drug discovery research (HTS format, reproducible and robust) and drastically reduce the associated costs and the number of animals used, in order to further increase the interest of the pharmaceutical industry for muscle disorders.

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  • Funder: European Commission Project Code: 839960
    Overall Budget: 159,815 EURFunder Contribution: 159,815 EUR

    African trypanosomes (Trypanosoma brucei, T. congolense, and T. vivax) are extracellular parasites responsible for animal African trypanosomiasis, a livestock disease in Africa and South America that results in frequent epidemics, substantial animal mortality and economic loss. Parasites evade the host immune system through the sequential replacement of their surface coat of variant surface glycoproteins (VSGs). In T. congolense, the VSG super-family is divided into 15 phylotypes, which may have new functions beyond immune evasion. In this fellowship, we propose that VSGs may be important in tissue tropism. Despite being considered blood parasites, African trypanosomes colonise other tissues. The extent of extravascular colonisation and its impact in parasite development remain poorly understood, even though tissue distribution is linked to disease severity and may contribute to the large phenotypic variability observed in clinical cases. In this fellowship, I aim to study antigenic expression in distinct tissue reservoirs. First, I will characterise tissue tropism of T. congolense and T. vivax by comparing gene expression patterns of their extravascular populations. Subsequently, I will investigate the role of individual T. congolense VSG phylotypes in tissue colonisation and disease progression. To achieve this, I will establish Clustered regularly interspaced short palindromic repeats (CRISPR)-associated gene 9 (Cas9) genome editing technology for the first time in T. congolense. I propose a multi-disciplinary approach combining computational, cell, and molecular biology to reveal species-specific adaptions to tissues and the impact that particular VSG phylotypes may have in establishing or maintaining those niches. I will show that VSGs, well known proteins in trypanosomes, play important roles in disease that go beyond the classical antigenic variation dogma.

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  • Funder: European Commission Project Code: 842695
    Overall Budget: 147,815 EURFunder Contribution: 147,815 EUR

    The need to preserve correct splicing is a major source of constraint on sequence evolution. This includes selection on the splice sites as well as on regulatory elements in exons and introns. Are all exons and introns constrained similarly by splicing related pressures? This is a crucial problem not only for understanding genome evolution but also for predicting where disease-causing mutations occur. Any variation in the prevalence of splicing information most likely reflects mechanistic variation in how the splicing process unfolds at different introns. Notably, it is often assumed that the relative importance of intronic and exonic splicing information depends on whether the splicing machinery recognizes introns or exons as the initial unit. However, this common model has never been tested directly because it is currently not possible to investigate splicing mechanism at this level of detail genome-wide. Existing studies on the distribution of splicing information are therefore based on proxies of unclear mechanistic significance, such as intron size. My host lab has developed a nascent RNA sequencing technique that allows unprecedented insight into splicing dynamics transcriptome-wide. They have recently applied this method to Drosophila melanogaster, a species thought to use a diversity of splicing strategies. I propose to use this data, combined with a machine learning approach, to conduct the first genome-wide study into exon and intron definition based on direct kinetic evidence. I will then use population genetics methods to determine how the prevalence and strength of selection on different types of splicing information covaries with splicing dynamics.

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  • Funder: European Commission Project Code: 101126073
    Overall Budget: 1,998,840 EURFunder Contribution: 1,998,840 EUR

    Adult stem cells (SCs) sustain tissue renewal and repair throughout life. The SC niche is fundamental in the regulation of SC function and an important contributor to SC decline in aging. While alterations in the tissue’s immune environment are emerging as important contributors to impairments found in aged organs, their contribution to SC dysfunction in aging is unknown. The skeletal muscle (SkM) is a paradigmatic model to study age-related loss of repair capacity. Muscle stem cell (MuSC) function during regeneration requires plasticity in transit between states of quiescence, activation and differentiation. MuSC functional impairments in aging result from changes in the extrinsic cues that govern their behavior, but also cell intrinsic alterations, including senescence and defects in lineage commitment. However, we still have a limited understanding of how changes in the environment manifest as SC intrinsic defects. Our previous work indicates that changes in immune signaling are important drivers of MuSC dysfunction and regenerative decline in aging. Here, we propose to identify the contribution of specific immune populations and signals to changes in regenerative capacity and MuSC activity in aging (Aim 1). We hypothesize that the immune environment is an essential regulator of MuSC plasticity and lineage commitment under regenerative pressure, and immune alterations underlie defects in MuSC lineage fidelity in aging. We propose to map the trajectories of MuSCs diverging from the myogenic lineage and uncover the changes in epigenetic landscape that underlie the loss of lineage fidelity associated with immune aging, identifying transcriptional regulators of MuSC fate (Aim 2). The knowledge generated on the mechanisms linking immune aging and MuSC dysfunction will be tested for the conservation in human SkM and will be applied to improve the success of MuSC-based therapies in aging (Aim 3).

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