Projects / Programmes
January 1, 2015
- December 31, 2021
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
secretory, vesicle, exocytosis, cytosolic, calcium, cAMP, glucose, lactate, membrane fusion, cellular edema, intelligent defficiency, Alzheimer's disease, neurodegeneration, diabetes
Researchers (49)
Organisations (2)
Abstract
CELL PHYSIOLOGY programme aims to understand the mechanisms by which cells communicate with each other in normal and pathologic conditions. Eukaryotic cells emerged 1-2 billion years ago and are characterized by subcellular organelles. These include SECRETORY VESICLES, storage for chemical messengers, playing an important role in cell-to-cell communication and are the OBJECT of our studies.
Rapid communication between neurons consists of the propagation of action potentials along axons to nerve terminals, where the merger between the vesicle and the plasma membrane is triggered. This process is part of the late steps of REGULATED EXOCYTOSIS and leads to the formation of a water filled fusion pore, which mediates the exit of molecules, stored in the vesicle lumen, into the extracellular space. Not only neurons, practically all eukaryotic cells exhibit exocytosis, and we will study several cell types, including pituitary cells, astrocytes, adipocytes and clonal cells to address questions related to:
i) VESICLE TRAFFIC AND MEMBRANE FUSION,
ii) CYTOSOLIC SIGNALLING AND METABOLISM,
iii) CELL PHYSIOLOGY IN DISEASE MODELS.
Although the Nobel Laureate B. Katz started to investigate exocytosis over five decades ago, the knowledge of this process is still fragmental, mainly due to experimental inaccessibility. We will use METHODS, including super-resolution microscopy and electrophysiology, which we introduced in our labs to monitor physiological parameters at cellular, single organelle, and at single molecule level together by using cell cultures, tissue slices and transgenic animal (disease) models to correlate the cell function to pathologic and therapeutic significance.
TRANSLATION. We strongly believe that this strategy will not only provide us with publishing in the highest visibility peer review papers as was the case in the past (J. Neuroscience, JBC, Neuron, Glia, Nature Drug Discovery Reviews, Nature Protocols, Nature Communications), but will also allow us to reach-out translational directions. During the last period we have been able to establish the lab GMP standards and developed (on the basis of membrane fusion experiments) an advanced cell-based medical product which entered into a clinical trial (EudraCT # 2012-005498-29). We will continue to file patent applications as we already have for the discoveries of platforms to screen for molecules targeting vesicle dynamics and metabolic changes in cells. The other aspect of translation is the dissemination of our results through education; we introduced new curricula at the University of Ljubljana (Fundamental Physiology, Molecular Physiology and Cell Engineering).
FEASIBILITY & IMPLEMENTATION. Our team consists of highly motivated researchers, working within a quality management system compliant with the ISO:17025 standard, and the Cell & Tissue Establishment regulations, both audited by the Slovenian Accreditation (EU Accreditation System) and by the National Agency for Medical Products an Devices.
Significance for science
We believe that the work we are proposing is significant on several different levels (the relevance of the investigated research objects in this proposal have been acknowledged by the recently awarded Nobel Prize in 2013). First, it is interesting in its own right, providing new information about ubiquitous biological processes - exocytosis, vesicle traffic, cytosolic homeostasis of second messengers and metabolites - that at present are not well understood. Second, these are model systems for the study of ‘functional genomics and proteomics’. That is, for most complex biological processes involving the specific interactions of dozens of different genes and proteins, it is not possible to monitor the process in real-time in living organisms. For this one has to use single cells and multiple techniques, which can be used either individually or simultaneously in combination to address questions related to the properties of functional modules that contribute to the function of cells and organisms as a whole, using also animal models of human diseases.
Unitary exocytic events in pituitary cells and astrocytes, which outnumber neurons in brain, can be studied in this way. Understanding vesicle dynamics prior and after exocytosis can also be studied in single cells such as astrocytes, which are increasingly viewed as essential elements in information processing in the central nervous system in health and disease. The cytosolic events involving second messengers and metabolites that are associated with vesicle traffic are poorly understood and optical techniques in combination with fluorescent molecular probes provide an approach that promises new important directions to be opened in the future. In particular with the advances in super-resolution microscopy, advanced electrophysiology, the use of optical nanosensors and others. All of these methods are introduced into our labs. In combination with tissue slices the function of single cells can be placed in the framework of a cell association and then into animal models of diseases.
Finally, it seems reasonable to hope that this work, while targeted to only a few types of diseases (cancer, neurodegeneration, intelligent dissability) will be useful for discovering new therapeutic processes and targets and thus helping to preserve and promote human health. Anterior pituitary hormones control bodily functions including growth, development, reproduction, and responses to stress. To understand neuroendocrine integration one needs to understand the mechanisms that control exocytosis. Therefore, the proposed research will not only examine fundamental physiological/biophysical aspects of exocytosis, vesicle traffic, cytosolic signaling with messengers and metabolites, but will additionally reveal new aspects of physiological regulation of hormone and neurotransmitter release, vesicle traffic and cytosolic homeostasis in terms of conditions related to cancer, neurodegeneration (Alzheimer’s Disease, Intellectual Dissability), brain trauma and diabetes.
Significance for the country
Cell Physiology represents an essential discipline for the development of new therapeutic and diagnostic methods in modern molecular medicine. Therefore, the strategy to support fundamental and applied research cell sciences represents a strategy to deliver and support a much more rapid development of the whole society, including that in Slovenia. Fundamental research is essential for the education of future experts and also the lay public. The latter needs to be educated in terms of understanding the new developments in cell biology and molecular medicine. For example: the promising new discoveries in stem cell research, subcellular physiology, cell engineering, cell-based therapy, the biology and mechanisms of diseases, the mechanisms of treatment, and others need to be presented to the public. Furthermore, solving problems in the context of universal problems at the highest possible methodological level is increasing the visibility, credibility and competence of the whole society. Expertise in the field of Cell Physiology, which has a tradition of several decades in Slovenia, also in the industry of biologicals, is necessary to support a more rapid development for Slovenia, contributing significance for global efforts with the family of other nations.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
Annual report
2015,
interim report
