28 Projects, page 1 of 6
The emerging field of immunometabolism has a strong potential to uncover novel targets for the manipulation of immune cell function. Myeloid cells are involved in innate and adaptive immunity and tolerance, therefore the identification of pathways that regulate their activity may have implications in many diseases. Research in the host laboratory has focused on how sensing of innate stimuli (infections and tissue damage) lead to mitochondrial adaptations in myeloid cells. These mitochondrial adaptations can influence the electron transport chain (ETC), resulting in differences in reactive oxygen species (ROS) production, ATP synthesis, redox balance and metabolites. The ETC consists of four respiratory complexes (CI-CIV), which can, excluding CII, form super complexes. The formation of these super complexes is regulated and this regulation has been shown to have biological relevance. However, whether mitochondrial SC organization couples to regulation of immune cell function and the molecular mechanisms involved is not known. Therefore, we propose to investigate how mitochondrial SC formation affects macrophage and dendritic cell function. Identification of the mechanisms connecting mitochondrial adaptations and myeloid cell function could potentially unveil therapeutic targets. Much immunometabolism studies could be improved by in vivo models, therefore we aim at studying the effects of SC formation regulation in vivo. We intend to use targeted and non-targeted approaches to address this question. A mouse model that exhibits a non-active SC assembly factor (SCAF1) will be a key tool to address this question in vivo. The non-independent approach includes state-of-the-art metabolomics and transcriptomics.
Cardiovascular disease (CVD) incidence continues to rise at an alarming rate largely as a consequence of behavioural risk factors. The only way to tackle this epidemic is to implement preventive strategies before the disease appears. Current evidence suggests that conventional approaches are inadequate for promoting healthier lifestyles, and therefore implementation of novel methods is desperately needed. The research proposed under the acronym of CLIP (Comprehensive Lifestyle Intervention Project) will tackle novel approaches to CVD prevention based on the Personalized Medicine concept, considering the interactions between genetic and environmental factors of disease development. During the outgoing phase (24 months), the young Experienced Researcher (ER) will perform extensive and multidisciplinary training on innovative strategies for effective lifestyle modification in adults and children, and will undertake a specific study to identify genomic factors able to predict adult subjects who will benefit most from novel lifestyle interventions, thus permitting future tailored approaches. During the incoming phase (12 months) the ER will transfer the new methodology to Europe by carrying out a pilot lifestyle modification and genomic study program in adults in Spain. This experience will be enriched by the secondment in a private multinational company. Thus, the new abilities the ER will acquire from various areas will enable him to implement new programmes to attain primary CVD prevention, including the use of genomic-driven personalized approaches; and to become an independent group leader upon my return to Europe at the host institution. The long term impact of the CLIP will help to reduce the huge economic burden to society and healthcare systems associated with CVD treatment as it will directly contribute to Europe’s aim of fighting the CVD epidemic.
Mature B cell neoplasias include most of Non-Hodgkin Lymphomas (NHL), such as Diffuse Large B Cell Lymphomas and Burkitt Lymphoma and also B cell Chronic Lymphocytic Leukemia. It is estimated that about 60000-80000 new cases of mature B cell neoplasias are diagnosed every year in Europe. About 60% of NHL present with aggressive forms, and need immediate therapeutic action. The most common choice of treatment for mature B cell neoplasia is chemotherapy, and particularly the multidrug R-CHOP, but a fraction of the cancers either are refractory to these therapeutic interventions or relapse after treatment. Indeed, NHL is the cause of close to 26,000 deaths per year in Europe. Therefore, alternative therapeutic targets are imperative to replace or complement the current approaches. microRNAs (miRNAs) have arisen as extremely promising therapeutic tools in a number of diseases, including cancer. We have identified a miRNA specific of mature B cells whose expression is lost in mature B cell neoplasias. We found that re-introducing this miRNA in lymphoma cells in animal xenograft models leads to a dramatic block of tumor growth and extends mouse survival. Our studies show that this miRNA is therapeutically efficient not only in the form of lentiviral vectors but also as a synthetic miRNA mimic. Likewise, both intratumoral and systemic, intravenous delivery of miRNA mimic have yielded positive regression results. In addition, established lymphoma cell lines as well as primary mature B cell lymphomas have proved sensitive to miRNA treatment. Therefore, we propose to take to proof of concept the idea that miRNA replacement is an efficient therapeutic strategy for the treatment of mature B cell lymphomas. With this HEAL-BY-MIRNA proposal we aim at moving forward this idea to a stage where it can be exploited to have social impact and to become a marketable product.
Protein mechanics is a key contributor to the form and function of biological systems by mechanisms that are just starting to be unraveled. An ensuing hypothesis is that alteration of protein mechanics can trigger disease, particularly in mechanical conditions such as cardiomyopathies in which primordial underlying molecular mechanisms remain elusive. Although tempting, this possibility has not been tested due to the absence of methods that can modulate the mechanics of proteins in vivo. My proposal aims to overcome technical barriers to scientific progress by establishing manipulation of protein mechanics in living cells and animals as a new research field. In aim 1, we will address current technological limitations through the generation of genetic, protein-engineering-based mechanical loss- and gain-of-function models to interfere acutely and reversibly with protein mechanics in living systems (mLOF and mGOF, respectively). We will apply these first-of-their-kind tools to the giant protein titin, a major contributor to the force-generating and sensing properties of cardiomyocytes with strong links with heart disease, and a workhorse protein that has been instrumental in the past to understand the biophysics of polypeptides under force. In aim 2, we will exploit cellular mLOF and mGOF to define how perturbations of titin mechanics result in altered cardiomyocyte force generation, mechanosensing, mechanotransduction, differentiation and proliferation. Leveraging on our cell studies, in aim 3 we will use murine mLOF and mGOF to shed light into the contribution of titin mechanics to the onset and progression of genetic and acquired cardiomyopathy. ProtMechanics-Live builds on our unique expertise in protein mechanics and engineering, biophysics, biochemistry and cardiovascular biology to enable investigation of mechanical proteins in their functionally relevant, physiological context
DILEMMA will orient fundamental research to fill a gap in diabetes mellitus (DM) biology, by addressing a relevant biomedical problem in a cross-disciplinary manner, with great societal and economic impact. I will use a unique combination of advanced nanoscopy with protein biochemistry and cell biology. Clinical studies identified stiffening in vascular, muscle and connecting tissues as particular mechanical fingerprints for DM. In diabetic patients advanced glycation end products are clinical biomarkers of DM that correlate with increased heart failure risk, but the mechanism of action bridging the mechanical alterations at molecular and tissue levels remains elusive. Current techniques used to inspect biochemical regulation of proteins fall short at describing the interplay between their dynamics under force and biological function. An in-depth multiscale characterization of the mechanical landscape in DM is a promising approach to identify new mechanical biomarkers able to advance therapeutic and diagnostic strategies. DILEMMA will study the fundamental link between tissue stiffening and protein glycation modifications in DM at multiple scales relevant for mechanobiology. I will explore the hypothesis that in diabetic patients lamin proteins are modified by glycation, which disrupts nuclear mechanical homeostasis. DILEMMA will have a strong impact in DM biology by providing new tools to understand how protein glycation and nuclear mechanics set the mechanical properties of cells and tissues in pathophysiological conditions. I will receive training and education to acquire or strengthen my technical, scientific, and soft skills. This action will impact my career, representing a jump that will advance my future goal of becoming an independent young leader and establishing a unique research line at national level. DILEMMA could improve future clinical practice and reduce economic burden on the health system.