Image Credits: © The Nobel Committe for Physiology or Medicine. Ill. Mattias Karlén
CiBB scientists congratulate the Nobel Prize awardees Victor Ambros and Gary Ruvkun for discovering a new class of small RNA molecules that play a crucial role in gene regulation: the microRNAs. We now know that microRNAS are relevant for how organisms develop, function and also in diseases. Several CiBB scientists have been investigating and using microRNAS.
Researchers from the Advanced Cell Technology group are leveraging miRNA libraries and high-throughput screening strategies to uncover miRNAs involved in key cellular processes. For instance, we recently identified miRNAs that enhance the survival of endothelial cells under ischemic conditions—an important finding for the field of regenerative medicine (Paper here). Additionally, we have submitted a manuscript detailing the discovery of miRNAs that protect pancreatic beta cells from glucolipotoxicity-induced cell death. As high levels of glucose and fatty acids are commonly associated with diabetes and obesity, identifying miRNAs that restore beta cell function is crucial for early detection of at-risk patients and for developing novel therapeutic strategies. However, identifying miRNAs is only part of the challenge—effective in vivo delivery remains a significant hurdle for clinical translation. To address this, we are exploring the use of extracellular vesicles, which are naturally secreted by most cells and serve as key mediators of intercellular communication, as vehicles for miRNA delivery (Papers here and here).
Researchers from the Gut-Brain axis group have been investigating the crosstalk between gut miRNAs and microbiome. Specifically, they aim to elucidate potential gut miRNAs contribution to Parkinson’s disease development and clarify its mechanistic interface in mitochondrial dysfunction and inflammatory responses, known to be involved in Parkinson’s disease pathogenesis (Paper here). More information can be found here.
Researchers from the groups Neuroendocrinology & Aging and Data-Driven Molecular Design are creating a comprehensive database of microRNAs that are affected by Obstructive Sleep Apnea (OSA), a common sleep disorder. Their work shows how OSA influences these tiny molecules, which play a role in various health issues, including heart disease and cancer. This new database will help us better understand how OSA contributes to these diseases and improve how we manage the condition in patients (Paper reference - (2024, submitted for publication): Laetitia S. Gaspar, Ana Capitão, Bárbara Santos, Alexandrina Ferreira Mendes, Cláudia Cavadas, Irina S. Moreira, Ana Rita Álvaro - Differential expression of microRNAs in Obstructive Sleep Apnea: a systematic review and pathway analysis).
Researchers from Neuronal Circuits and Behavior showed that the microglia pro-inflammatory profile observed in Alzheimer’s disease is associated with the deregulation of a specific miRNA, miR-155. These researchers also identified other immune-related miRNAs whose levels are downregulated, systemically, in AD and mild-cognitive impairment patients. This miRNA deregulation profile is correlated with defects in important immune functions, including monocyte-mediated chemotaxis and macrophage-mediated phagocytosis, highlighting the contribution of miRNAs to the regulation of innate immune response (Paper here and here).
Researchers from the Obesity, Diabetes and Complications group have been investigating the role of microRNAs in different fields of Diabetes and their related complications. In prepubertal children with obesity, they have identified altered circulating microRNA levels in the early stages of insulin resistance (Paper here). Several contributions have also been achieved in the diabetic foot ulcers (DFU) field, from the discovery of a microRNA as a promising therapeutic target, using a diabetic mouse model (Paper here), to the evaluation of the role of microRNAs as wound-healing physiological indicators in patients with chronic DFUs presenting psychological distress (Paper here and here). They have also highlighted the “New Insights in Diabetic Foot Ulcer Mechanisms: DNA Methylation and Non-coding RNAs. Rev. Port. Diab. 2024, 19, 2, 60-71”. They have also been working towards the characterization of epicardial adipose tissue microRNAs as modulators of the cardiovascular system (Paper here).More recently, they have identified an unique epicardial adipose tissue microRNA transcriptome in patients subjected to cardiac surgery (in preparation).
The research groups RNA & Infection and Functional Genomics and RNA-based Therapeutics pioneered the application of high-content microscopy screenings to identify microRNAs controlling infection by bacterial pathogens. For example, we have discovered that infection of epithelial cells by two bacterial pathogens Salmonella Typhimurium and Shigella flexneri are controlled by largely non-overlapping subsets of microRNAs, which has led to the discovery of novel molecular players relevant to the host-pathogen interplay (Papers here , here and here ). We have also been investigating the impact of bacterial infection on the host miRNome expression and the molecular mechanisms underlying microRNA regulation by bacterial pathogens (Papers here and here).Over the last 10 years, the Functional Genomics and RNA-based Therapeutics group has been exploiting the regulatory role of microRNAs in multiple biological processes (Papers here , here and here), with a focus on cardiovascular disease biology. By performing microscopy based high-throughput screening using genome-wide libraries of microRNAs, we have identified microRNAs critical in controlling cardiac repair, cardiac regeneration, and cardiac fibrosis-related phenotypes. Given the pleiotropic mechanism of action, microRNAs are particularly attractive for the development of novel therapeutics targeting complex diseases.
Researchers from the Synapse Biology group have been working towards understanding how miRNAs impact the function and structure of synapses, the communication hubs between neurons. They have uncovered that miR-186-5p plays a crucial role in regulating the mechanisms responsible for maintaining stable neuronal and circuit function in the brain, during development and learning, by modulating the levels of neurotransmitter receptors (Paper here). More recently, the group has been focused on unravelling the link between the increased miR-186-5p levels and the neuronal dysfunction underlying behavioural and cognitive deficits caused by chronic exposure to stress.
The work carried out in the research group Vectors, Gene and Cell Therapy has brought encouraging results that demonstrate the relevance of microRNAs in the treatment of neurodegenerative diseases, such as Machado-Joseph disease (MJD), one of the research team's focuses. The main results led to publications in top scientific journals. By modulating the levels of specific microRNAs (miRNAs) using a gene therapy-based approach, it was possible to reduce the severity of the neuropathology of Machado-Joseph disease (MJD) in a lentiviral (LV) mouse model. Expression of the let-7 miRNA in the mouse brain was sufficient to reduce aggregation of neuronal proteins and significantly increased LC3-II levels, thus indicating that let-7-mediated activation of autophagy is beneficial for MJD (Paper here) . Furthermore, overexpression of mir-9, mir-181a and mir-494, which are predicted to target the ataxin-3 (ATXN3) 3'UTR and are abnormally downregulated in MJD models, effectively reduced ATXN3 mut levels and improved MJD-associated neuropathology (Paper here). In addition, adeno-associated virus (AAV)-mediated administration of an artificial miRNA against ATXN3 almost completely relieved intracellular ATXN3 inclusions and restored neuronal function (Paper here). Work in this area continues, so keep an eye out for further news.
As stated on the official award website “Tiny RNAs with profound physiological importance: Victor Ambros and Gary Ruvkun discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery in the small worm C. elegans revealed a completely new principle of gene regulation. This turned out to be essential for multicellular organisms, including humans. MicroRNAs are proving to be fundamentally important for how organisms develop and function.”. Here you can find the Press Release about the 2024 Nobel Prize in Physiology or Medicine.
