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Description
Diabetes is one of the fastest growing health challenges of the 21st century, characterized by chronic hyperglycaemia due to the inability of the body to produce and/or use sufficient insulin. Despite major advances, self-management of diabetes remains challenging. In diabetes, the cellular protection mechanism fails without relieving the burden and ultimately the cells die. Our project aims to characterize these cellular protection mechanisms during diabetes progression. We plan to define the stress threshold that β-cells withstand without being affected irreversibly. Moreover, we will use the results to design strategies to modulate the protection mechanisms to get a better response of β-cells to sustained stress. We plan to achieve a clinically relevant therapeutic approach to regenerate β-cells function from diabetic pancreas. This is aimed at helping the β-cells’ secretory performance by improving their capacity to cope with increased load, thus restoring insulin levels. Our strategy will have an important impact, helping design better treatments for management of diabetes. We envisage that our collaboration will establish a long-term partnership between ICBP “N. Simionescu” and University of Bergen. We expect it will promote the translational research impact of both groups, while also expanding their research capacity by increasing the number of young researchers trained in a high-quality scientific environment. This will ultimately enhance the research performance in the Romanian Institute and increase young Romanian scientists’ potential of for further applications to EU framework programmes calls and other international funding sources.
Summary of project results
The BetaUPReg project tackled a key issue in diabetes: the failure of β-cells, that are producing insulin. Current diabetes treatments mainly focus on controlling blood sugar and using external insulin, without addressing the stress and damage happening inside the β-cells. There is a big need for new treatments that can help these cells survive and function better, potentially leading to better management or even a cure for diabetes. In β-cells, the constant demand for insulin causes stress in a compartment of the cell called the endoplasmic reticulum (ER), leading to a protective reaction known as the unfolded protein response. Normally, this mechanism helps the cells recover, but if the stress is too strong and too long, it can backfire and cause the cells to die. BetaUPReg project aimed to understand how unfolded protein response works in β-cells and to develop new ways to help these cells handle stress. The goal was to find treatments that help the cells manage stress better, proliferate and prevent the cell death. By focusing on the root cause of β-cell problems —the ER stress— the project hoped to create breakthrough treatments that go beyond just managing symptoms and actually address the disease at its source.
The BetaUPReg project focused on advancing understanding of β-cell dysfunction in diabetes through targeted research on the unfolded protein response (UPR). Key activities included extensive experiments using transgenic mice (RIP-DTR, βHnf1a), which facilitated innovative approaches to study β-cells’ response to metabolic stress. In addition, NOD (model for autoimmune diabetes) and streptozotocin-treated mice were used. The mice were subjected to different conditions, including high-fat diet, to simulate the stress that human β-cells undergo in diabetic patients.
A significant output of the project was the development and validation of new models for predicting β-cell behavior under stress. Through this collaboration, researchers successfully characterized the adaptation mechanisms of β-cells, using techniques like RNAseq and immunofluorescence to analyze cellular responses. These methodologies yielded a substantial amount of data on insulin production and cell survival, leading to joint publications, such as "Modulation of UPR Restores Survival and Function of β-Cells Exposed to the Endocrine Disruptor Bisphenol A". Unexpectedly, the project also discovered that certain β-cell populations were more resilient to stress than previously understood, suggesting new pathways for therapeutic intervention. This insight has opened up further research avenues and underscored the potential for developing more effective diabetes treatments based on enhancing natural cellular resilience.
The BetaUPReg project achieved significant advancements in understanding β-cell dysfunction in diabetes through a series of targeted investigations and developments. One main achievement was the subcellular characterization of β-cells under various stressful conditions, which deepened our comprehension of how these cells respond to, manage, and adapt to stress. This understanding is crucial for designing potential therapeutic interventions aimed at alleviating β-cell stress in diabetic patients. Mapping the molecular landscape of β-cells during diabetes progression in NOD mice, identified critical factors like Atf3 and elements of the Hedgehog signaling pathway influencing the inflammatory environment and β-cell regeneration. Moreover, various mechanisms of β-cell adaptation to stress were described.
Researchers developed new transgenic mouse models and detailed molecular data that provide a richer understanding of diabetes pathology. Data from BETAUPREG project offers clinicians insights that could lead to more effective treatment options based on enhancing β-cell resilience. Patients could be provided improved diabetes management options, potentially reducing the burden of the disease. These contributions underline the project''s impact in advancing diabetes research and therapy, offering valuable pathways for clinical applications and further scientific exploration, driving development of novel strategies to enhance β-cell mass and function, essential for maintaining insulin production under stress.
Summary of bilateral results
The BetaUPReg project fostered strong collaborative ties between institutions in Norway and Romania, enhancing the scientific capabilities of both and establishing a durable partnership. This cooperation facilitated a rich exchange of scientific knowledge, methodologies, and resources such as unique transgenic animal models and advanced molecular analysis techniques. The collaborative framework not only propelled the project''s research objectives but also set the stage for continued joint efforts beyond the project''s timeline. The partnership has been instrumental in pooling expertise from different backgrounds to tackle complex biomedical challenges effectively, contributing to the strengthening of the European Research Area. Additionally, joint publications and participation in international conferences have solidified this relationship, showcasing the success of collaborative ventures funded by the Grants and setting a precedent for future cross-border research initiatives.