RO-NO-2019-0544
Supportive therapy for diabetes by increasing the stress endurance and regenerative capacity of β-cells
"WORKING TOGETHER FOR A GREEN, COMPETITIVE AND INCLUSIVE EUROPE"
"WORKING TOGETHER FOR A GREEN, COMPETITIVE AND INCLUSIVE EUROPE"
1. Subcellular characterization of the early secretory pathway of the β-cells during progression of diabetes, or through various stressful conditions.
This was imperative because it deepened the understanding of the β-cell stress response, how it handled this stress, and how it adapted. By identifying the timing of the structural modifications that occur in these cells, and following them after the various interventions aimed to aggravate, or to alleviate the stress, allows to better define the potential therapeutic interventions.
2. In depth molecular characterization of the islet response to either (1) early insulitis during diabetes onset in the NOD mice, or (2) mild ablation in the RIP-DTR 50% system, in the absence or presence of additional insults.
This was of crucial importance for identifying key factors responsible for decreased proliferation, increased stress, enhanced regeneration that can be targeted in an attempt to support or recover the necessary β-cell mass for insulin requirements.
3. Enhanced understanding of β-cell functional heterogeneity.
Significant strides have been made in mapping out the varied responses of β-cells to different stressors. By identifying diverse β-cell populations and their unique reactions to environments like increased inflammation (in the NOD mice), high-fat diet, increased glucose exposure, or chemical stressors, our project has provided valuable insights into cellular mechanisms that could be targeted for therapeutic intervention.
4. Characterization of the β-cell response upon activation of the UPR branch, Atf6, through AA147.
By identifying the mechanisms underlying this response, we underline the importance of UPR in β-cell homeostasis.
5. Systematic characterization of the UPR response of differentiated 3D islets organoids from human induced pluripotent stem cells exposed to various stressors.
Importance: These insights are crucial as they lay the groundwork for potential therapeutic targets and strategies to enhance β-cell resilience and function. For example, the identification of different β-cell populations and their responses to various stressors like high-fat diets helps in tailoring more precise therapeutic approaches.
Project financed by Norway Grants 2014-2021 and operated by UEFISCDI.
Elena Lamba, PhD student
Ana Mardare, MSc
Sabin Popa, MSc
June Gudmestad, MSc