The GENIUS II (Generating Evidence-Based Pharmaceutical Targets and Drugs for Atherosclerosis) consortium is dedicated to studying atherosclerosis, the primary pathological condition underlying cardiovascular diseases. The consortium aims to translate identified druggable targets for atherosclerosis intervention into clinical applications. Gender specificity is a key consideration in all our studies. Our consortium's talent program is structured to provide young researchers with insights into the opportunities and challenges of cardiovascular drug development.

The Research
GENIUS II research integrates knowledge of dyslipidemia and associated immune responses. Our work is organized into distinct work packages that correspond to the logical steps in drug development. Each selected target from GENIUS I is strategically incorporated into this framework. Our investigations encompass in vitro and in vivo analyses to understand mechanisms, druggability, and effects on atherosclerosis.

In addition to building upon GENIUS I drug targets and leads, we leverage recent innovative advancements to identify new druggable targets within male and female atherosclerotic lesions, as well as in circulating cells. State-of-the-art molecular biology techniques, including single cell sequencing and immunophenotyping, are actively employed to dissect immunometabolic processes within atherosclerotic plaques and patients. These studies will enable us to monitor the presence of drug targets at disease sites, expediting drug design and potentially identifying gender-specific biomarkers to aid disease progression monitoring and diagnosis.

Subsequent studies involve testing the efficacy of small molecules, monoclonal antibodies, and siRNA against pre-selected targets from GENIUS I. We have identified small molecules and monoclonal antibodies for five targets, which will undergo toxicity and proof-of-pharmacology studies to progress towards drug development for cardiovascular patients. We have also identified three drugs affecting primary targets from GENIUS I and are assessing their potential to reduce atherosclerotic parameters in First-In-Human clinical trials.

This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation. The GENIUS II consortium builds on the most promising targets identified in the GENIUS I consortium, with the goal of advancing these targets towards clinical application.

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Heart failure represents a significant healthcare challenge due to its high morbidity and mortality rates. Historically, the emphasis has been on heart failure with reduced ejection fraction characterized by left ventricular dilation. However, nearly half of heart failure patients involve diastolic dysfunction due to heart chamber stiffening, known as diastolic heart failure or HFpEF. The Focus Research conducted by our consortium indicates that impaired kidney function is an is a strong risk factor for HFpEF. Patients with chronic kidney disease are more prone to developing HFpEF and have higher mortality rates from associated complications. The specific mechanisms by which even slight declines in renal function worsen cardiovascular risk and impact the development and prognosis of HFpEF are not yet fully understood. Insights from RECONNECT highlight the pivotal role of systemic inflammation and microvasculature in this context. The Research RECONNEXT (Renal connection to microvascular disease and HFpEF: the next phase) is a multicenter consortium dedicated on advancing medical research on heart failure - particularly heart failure with preserved ejection fraction (HFpEF) - in relation to impaired kidney function. Specific pre-clinical and clinical research objectives have been defined: Identify renal drivers for HFpEF onset and progression in subgroups/clusters of HFpEF patients, taking patient-specific risk profiles into account. Deepen our understanding of the mechanistic pathways involved in the pathogenic cross-talk between renal drivers, systemic inflammation, microvasculature, and cardiac cells leading to HFpEF, using dedicated ex vivo bioassays to assess patient material and in vivo small and large animal models. Investigate the most promising therapeutic targets in newly developed and well-characterized state-of-the art rodent and porcine models of CKD-associated HFpEF, taking comorbidities into account. Investigate the most promising therapeutic, diagnostic and prognostic candidate(s) in well-defined patient-groups by taking a stratified approach. We expect that the results of this project will enhance our mechanistic insight in the renal drivers of HFpEF development and progression and will lead to the development of personalized diagnostic, prognostic and therapeutic solutions for HFpEF patients. The origin The RECONNECT consortium has provided fundamental knowledge on the connection between chronic kidney disease and HFpEF and established a translational pipeline for the discovery and evaluation of potential diagnostic, prognostic and therapeutic targets. RECONNEXT builds upon the success of RECONNECT, established in 2015 (see Figure 1 below), supported by CardioVasculair Onderzoek Nederland (CVON) and the Dutch Heart Foundation. The RECONNEXT consortium consists of nephrologists, cardiologists, general practitioners, and scientists from five leading academic centers in the Netherlands (UMC Utrecht, Erasmus MC, UMC Groningen, Amsterdam UMC, Leiden University) renowned for their expertise in heart failure, vascular biology, and chronic kidney disease.    
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Right Heart Care In the Right Place

Atrial fibrillation and heart failure are two of the major cardiovascular challenges of our time. It is important that these conditions are detected in time and treated according to guidelines. This is far from always the case. It is sometimes not clear that certain symptoms are caused by atrial fibrillation or heart failure, neither to the patient himself nor to health care providers. As a result, it sometimes takes a long time before someone receives the right treatment. The chronic nature of heart diseases such as atrial fibrillation and heart failure also means that patients with these conditions are seen by many healthcare providers. To achieve this in a high-quality and transparent manner, optimal cooperation between the various care domains is necessary. It is important that the principle of right care in the right place (JZOJP) is applied. However, network care is complex and the effective organization of JZOJP by the right healthcare professional is still far from commonplace despite the many initiatives. The origin Better treatment of these conditions was a priority on the cardiovascular disease research agenda. This is why the Dutch Heart Foundation and ZonMw have started the thematic collaboration “Right Heart Care In the Right Place". By combining expertise, we want to detect as many people as possible with atrial fibrillation and heart failure early and treat them optimally. We are doing this in various ways: jointly setting up subsidy rounds to support regional collaborations, supporting a national support structure for the regions and overarching activities that contribute to knowledge development. As part of Right Heart Care In the Right Place, the network program of the Dutch Society of Cardiology, NVVC Connect, together with involved network partners, facilitates an adequate national support structure for affiliated regional collaborations, or Connect regions. The Connect regions are supported and guided in, for example, preparing the subsidy application and they receive support during the implementation of the regional transmural agreements. The research The Right Heart Care In the Right Place consists of two forms of support: the National Impulse: the aim is to set up a sustainable national support structure that stimulates and guides regions in the regional design and implementation of network care in the field of atrial fibrillation and heart failure the Regional Impulse: the aim of the Regio-Impulse Cardiac Care is to support regional alliances, the Connect regions, in implementing regional transmural agreements. By bringing together the various care providers from the 3rd, 2nd and 1st line, these collaborative ventures jointly offer cardiological care for atrial fibrillation or heart failure more integrally and transmurally. In this way, the patient comes into contact with the healthcare provider who can best contribute to the care need at that moment. A maximum of 22 Connect regions can receive funding to implement the transmural agreements or to optimize the implementation in their region.
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