Molecular mechanisms of Covid-19 and acute respiratory distress syndrome
Covid-19 pandemic has inspired hundreds of scientists around the world to find new ways to prevent and treat the viral disease. The main cause of death due to Covid-19 was quickly identified. It is an acute respiratory distress syndrome. So, to save a patient, one needs to understand the mechanisms of this syndrome! And it seems to us that we are on the right track, when exploring neutrophil extracellular traps! This is one of the mechanisms of phagocytosis, which is based on the release of DNA into the extracellular space. And the key enzyme in this process is protein kinase C beta, the activity of which we can already block; but there is still much work to be done.
Cellular and molecular mechanisms of signal processing by spinal cord neurons
Lamina I (Agashkov et al., 2019) and lamina X (Krotov et al., 2022) neurons of the spinal cord are responsible for processing of somatosensory and visceral nociception, respectively. They receive peripheral input signals, process and transmit them to the supraspinal centers, which form a sensation of pain. Although the responses of spinal cord neurons to afferent stimulation have been carefully studied, the mechanisms of decoding these signals and their modulation by the local neuronal networks and descending pathways are almost unexplored. In our studies, we use ex-vivo spinal cord preparation for electrophysiological, optical and genetic studies of synaptic and cellular mechanisms that determine the specific characteristics of the processing of sensory and pain information by these neurons.
Molecular Pharmacology of TRP channels
Transient receptor potential (TRP) cation channels, which research was awarded by the Nobel Prize in 2021, are a superfamily of polymodal cellular sensors that are expressed in almost all mammalian cell types and involved in numerous important physiological functions. Among the wide variety of TRP channels, our study is focused on TRPC4 in intestinal smooth muscles and TRPV4 (Tsvilovskyy, et al, 2009) and TRPM8 in vascular tone regulation (Dryn, et al, 2016; Melanaphy, et al, 2016). These channels are promising molecular targets for the correction of intestinal and vascular disorders and for designing of perspective and effective drugs. Moreover, we elucidate the role of these channels in the development of gastrointestinal and vascular side effects of widely-used anesthetics and analgesics (Dryn, et al, 2018; Melnyk, et al, 2020). Our experiments are performed on freshly isolated smooth muscle cells using patch-clamp and calcium imaging methods, and on muscle preparations using tensiometric techniques.
Signaling of Neuronal Calcium Sensor (NCS) proteins
Structurally similar NCS proteins, Neurocalcin δ (NCALD) and Hippocalcin (HPCA), control many neuronal processes including slow afterhyperpolarization (sAHP) and long-term depression (LTD). Both sAHP, which tunes neuronal activity, and LTD, which regulates the synaptic strength, are likely controlled by Ca2+-dependent HPCA and NCALD translocation from the cytosol to the plasma membrane (Dovgan et al., 2010)(Sheremet et al., 2020). Translocation abnormalities are also a basis for the development of neurodegenerative diseases (Osypenko et al., 2019). Ca2+-dependent signaling of these proteins, which regulates the functioning of neurons, is an important area of our research.
Role of long non-coding RNA in pathogenesis of post-traumatic stress disorder
PTSD, posttraumatic stress disorder, is a relatively new nosological unit, occurring most often during the war; thousands of Ukrainians are already suffering from it, and what exactly is happening in the brain during PTSD is still unknown. Therefore, the effectiveness of treatment of this mental disease is low. We have focused our studies of this syndrome on long non-coding RNAs, the most important intracellular regulators of all cellular processes. Now we are testing a hypothesis that changes in the expression of these molecules are a key to the development of PTSD.
Mechanisms of chronic pain development and maintenance
Pain is an unpleasant sensation that we try to avoid. At the same time, it has an important protective function, limiting the use of the damaged organ. But sometimes this mechanism fails, and the pain becomes chronic, significantly interfering with normal life. The molecular and cellular mechanisms underlying the development and maintenance of chronic pain at the level of functioning of peripheral sensory neurons are still insufficiently studied and are the subject of our attention (Duzhyy et al., 2021).
Development of computer algorithms for optimization of senolytic therapy
Senolytics are a new class of drugs for prolonging life and slowing down aging. Their target is senescent cells. Haven't heard anything about them? This is normal, because this direction of research is very new and now there are many more questions than answers in this field! New senolytics are described and created every month, there will be many of them. However, there is an unresolved question: who is prescribed which senolytic? People are different! For the first time in the world, we have started to individualize senolytic therapy and are developing a computer program that will help doctors prescribe treatment correctly according to artificial intelligence algorithms.
Development of novel methods of tissue engineering
Peripheral nerve injury (PNI) is a significant medical and social problem because it is characterized by long-term limb dysfunction and a high level of disability. Treating PNIs represents a major challenge in reconstructive surgery and regenerative medicine. The aim of our research is to determine the effectiveness of novel types of scaffolds for sciatic nerve regeneration in the treatment of PNIs. A biomimetic nerve engineering strategy is being implemented to prepare three-dimensional oriented functionalized scaffolds to recapitulate the architecture and biological function of the native sciatic nerve. The 3D printed scaffolds containing separate matrices for outgrowth of vessels and axons will be developed and tested for supporting a sciatic nerve regeneration and functional recovery after PNI in rats. As a result of the project, we expect to develop novel technology for the treatment of PNI in humans already tested at a preclinical level of its implementation.
Development of new optical and optogenetic approaches
In this project we are developing new approaches to study native spinal cord preparations (ex vivo and in situ). Current research requires patch clamping and digital imaging in samples of arbitrary thickness such as the whole spinal cord or bran. It necessitates further development of new optical approaches (e.g. lateral infrared light illumination (Szucs et al., 2009, Krotov et al., 2017, Agashkov et al., 2019)), optical stimulation of different types of primary afferents and descending fibers in genetically modified animals, and the simultaneous registration of the activity of a large number of neurons during the processing of input sensory signals. These methods are not commercially available and require thorough bioengineering work for their development and implementation.