ERC FUNDED PROJECTS

Health care practitioners face daily questions and make choices regarding the effectiveness and quality of several health technologies (e.g. alternative interventions). On this regard they usually consider meta-analysis; the statistical synthesis of results from relevant experiments. The main drawback of the current state of the art is that meta-analysis focuses on comparing only two alternatives. However, clinicians and scientists need to know the relative ranking of a set of alternative options and not only whether option A is better than B. There is an urgent need to establish and disseminate a robust framework for selecting among many treatment options, possibly after taking into account environmental and genetic interactions. The goal of the proposed project is to provide this by establishing and disseminating a revolutionary evidence synthesis toolkit. Its main methodological vehicle is a flexible statistical framework using Bayesian techniques for multiple-treatments meta-analysis. This will enable the relative ranking of all alternative health care options, will allow comprehensive use of all available data, will improve precision and confidence in the conclusions and will answer methodological questions related to bias. Once established in clinical epidemiology, the tool will be extended to genetic epidemiology to account for multiple genetic markers, environmental factors and effects of treatments. Based on ongoing collaborations with teams undertaking applied health care research I plan to evaluate the new tool empirically in real-life health care problems such as ranking the pharmacological treatments for osteoarthritis, indicating the best treatments for multiple sclerosis and ranking the vaccines for influenza.

592 500 €

Start date: 2010-10-01, End date: 2015-12-31

NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs. The main objectives are: 1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells. 2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications. 3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy. Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.

1 993 575 €

Start date: 2019-02-01, End date: 2024-01-31

Our understanding of Parkinson’s disease (PD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic, most frequent, form of PD. It may be possible to overcome these challenges by reprogramming somatic cells from patients into induced pluripotent stem cells (iPSC). In preliminary studies, we have generated a collection of 50 iPSC lines representing both sporadic PD and familial PD patients, and identified distinct PD-related neurodegeneration phenotypes arising, upon long-term culture, in DAn differentiated from these PD-iPSC. Here, I propose to take advantage of this genuinely human PD model to investigate: i) mechanistic insights responsible for the PD phenotype identified in our model (by combining molecular and biochemical analyses to study mitochondrial function and redox profile, as well as genome-wide transcriptional profile of control versus PD-patient specific iPSC-derived DAn); ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients (by electrophysiological recordings in in vitro reconstructed neuronal/glial networks to assess synaptic dynamics together with neuronal excitability); iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells. These studies may impact significantly on our understanding of PD pathogenesis and on the development of new therapy strategy.

1 324 802 €

Start date: 2013-07-01, End date: 2018-06-30

"Long-term objectives are to identify optical signals that control accommodation and emmetropization of the eye, and to identify the mechanisms that mediate the optical signals. A primary goal is to determine whether accommodation responds to the wavefront characteristics of light [defocus and higher-order aberrations (HOAs)], without feedback from change in defocus astigmatism or HOAs. Accommodation, pupillary responses and aberrations will be monitored by an imaging simulator that incorporates Hartmann-Shack wavefront sensing, adaptive optics and Hirschberg x-y eye tracking. Adaptive optics and Badal optics will compensate for the refractive error of the eye, alter or remove HOAs, and remove feedback from changes in accommodation and/or HOAs. Accommodation will be driven by defocus with normal HOAs present or removed. To determine whether accommodation responds to wavefront aberration per se, or simply to the shape or skewing of blur, aberrations will be removed while simulation of defocus targets are imaged on the retina, with and without the effects of HOAs on the blur. Standard model that accommodation operates as a closed-loop negative feedback system to maximize the contrast retinal image, will be tested by using adaptive optics to remove defocus, astigmatism and HOAs and by establishing a closed feedback loop between accommodation and target contrast. An alternative hypothesis that accommodation responds to wavefront defocus rather than blur of the retinal image, will be tested by driving accommodation with defocus without feedback from blur, in the absence of HOAs. A final experiment will determine whether the pupil changes independently of lenticular accommodation to provide better acuity in the presence of spherical aberration. Better understanding of the optical signals and mechanisms that the eye used to detect myopic and hyperopic defocus may lead to early detection of individual at risk for developing myopia, and new treatments to prevent/reduce myopia"

1 384 200 €

Start date: 2012-11-01, End date: 2017-10-31