Escola Paulista de Medicina
Postgraduate Program in Pharmacology

CELLULAR AND MOLECULAR PHARMACOLOGY AND PHYSIOLOGY: Projects

Projects of the CELLULAR AND MOLECULAR PHARMACOLOGY AND PHYSIOLOGY Research Line of the Postgraduate Program in Pharmacology:

PHARMACOLOGICAL AND MOLECULAR BASES OF AUTOPHAGY AND ITS CONTRIBUTION TO METABOLIC DISEASES, CANCER AND NEURODEGENERATION

PHARMACOLOGICAL AND MOLECULAR BASES OF AUTOPHAGY AND ITS CONTRIBUTION TO METABOLIC DISEASES, CANCER AND NEURODEGENERATION

Autophagosomes play an important role in the cell recycling process through the mobilization of lipids or proteins to the lysosomes via autophagy with subsequent degradation of these lysosomal hydrolases. This process, called autophagy, can be controlled through the EB transcription factor (TFEB), an important autophagy regulator, which can be functionally activated by the release of lysosomal Ca2+ in response to some alteration in cell metabolism. Nicotinic acid adenine dinucleotide phosphate (NAADP) has been postulated as an important cellular second messenger activating Two-Pore Channels receptors (TPC1 and TPC2 isoforms) located in the endolysosomal system. Activation of TPCs by NAADP causes the release of Ca2+ contained in lysosomes, inducing autophagy and regulating vesicular traffic. In this project, we aim to understand the lysosome-mediated pathway controlled by NAADP signaling in the context of cellular models, thus providing new evidence on how autophagy can be regulated in metabolic diseases, cancer and neurodegeneration, respectively. Experiments to assess pathways related to autophagic flow, TFEB signaling and metabolism will be carried out in these cell models. The morphology and functionality of autophagosomes and lysosomes will be evaluated by confocal microscopy and electron microscopy. This study highlights the importance of TPC-mediated autophagy, contributing to the development of new therapies.

Professor: Gustavo José da Silva Pereira

STUDIES ON THE ANTI- AND PRO-INFLAMMATORY, DEGENERATIVE, AND REGENERATIVE EFFECTS OF PHOSPHOLIPASES A2 ISOLATED FROM VIPERID SERPENTS, WITH EMPHASIS ON THE CHARACTERIZATION AND REGULATORY ROLE OF LIPID MEDIATORS ON THESE EFFECTS

STUDIES ON THE ANTI- AND PRO-INFLAMMATORY, DEGENERATIVE, AND REGENERATIVE EFFECTS OF PHOSPHOLIPASES A2 ISOLATED FROM VIPERID SERPENTS, WITH EMPHASIS ON THE CHARACTERIZATION AND REGULATORY ROLE OF LIPID MEDIATORS ON THESE EFFECTS

Secreted phospholipase A2 (sFLA2), isolated from snake venoms of the Viperidae family, such as Crotalus and Bothrops, have potent myotoxic and inflammatory action, respectively. On the other hand, in parallel to the myotoxic effects, it was demonstrated that the crotoxin complex, a toxin isolated from crotalic venom and formed by an sFLA2 subunit, when injected subcutaneously, inhibits inflammatory events such as leukocyte influx and edema. However, knowledge of the mechanisms that govern the phases of tissue degenerative and regenerative processes, after injury, as well as possible pro- and anti-inflammatory effects, all promoted by the injection of isolated sFLA2s, is still fragmented. In general, degeneration and tissue regeneration events are usually accompanied by an inflammatory response, characterized by the migration of leukocytes and secretion of inflammatory mediators, such as chemokines, cytokines, growth factors and reactive oxygen species. Studies have already shown that the nature, duration and predominance of inflammatory mediators, after the injury and during the repair process, are determinant in the quality of the restored tissue, which can be successful, or alternatively, due to the formation of fibrosis, it can lead to to loss of tissue function. Given the complexity of the inflammatory response, little research is noteworthy about the role of another important group of mediators, which include eicosanoids, arachidonic acid (AA)-derived metabolites, and also omega-3 fatty acid-derived mediators , such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), during post-injury tissue repair events. Since these mediators act both on tissue development and proliferation, as well as on hyperalgesia and inflammation, it is possible to hypothesize that they may affect the quality of regeneration of injured tissues, by influencing the differentiation of quiescent cells, regulating both expressed transcriptional factors and the components of the inflammatory response secreted in the distinct phases of tissue regeneration. In this context, the characterization of the production profile of the various types of anti- and pro-inflammatory lipid mediators, as well as their role in the different phases between tissue degeneration and regeneration, may configure new biomarkers of tissue-cellular repair. In a broader sense, the better characterization of degenerative and regenerative scenarios triggered by sFLA2s, in addition to expanding the knowledge of the role of the inflammatory response on myotoxic and inflammatory activities, can also make them useful tools for studies of tissue regeneration. In addition, studies with sFLA2s may contribute to the knowledge of new biological targets and/or prototype molecules for the design of new drugs with anti-inflammatory activity. Furthermore, knowledge of the influence of lipid inflammatory mediators in these processes may contribute to the development of new therapies for efficient tissue repair after injury.

Professor: Vanessa Moreira

ESTROGEN RECEPTORS SIGNALING MECHANISMS IN PROSTATE AND TESTICULAR CANCER

ESTROGEN RECEPTORS SIGNALING MECHANISMS IN PROSTATE AND TESTICULAR CANCER

Prostate cancer is the second most common cancer in men. Androgens, estrogens and stromal-epithelial interactions are involved in the development of prostate cancer. Prostate cancer initially responds well to androgen-deprivation therapies, but the majority of tumors evolve from an androgen-sensitive to an androgen-independent form of the disease, also known as castration-resistant prostate cancer (CRPC). At this stage, current therapies scantily improve survival of the patient.

Testicular germ cell tumors, seminoma and embryonal carcinoma (non-seminoma), are the most common form of malignant solid tumors in young adult men and their incidence is continuously increasing. The development at the time of puberty these testicular tumors suggests that the induction of proliferation of in situ carcinoma cells are sensitive to hormones. Androgen is not involved in this process, estrogen could play a role.

Thus, the main research focus in our laboratory is the estrogen receptors: expression, intracellular signaling and function in androgen-independent prostate cancer cells and testicular cancer cells.

Professor: Catarina Segreti Porto

MELANOCYTE MALIGNANT TRANSFORMATION AND MELANOMA PROGRESSION: THE ROLE OF CELLULAR STRESS AND EPIGENETIC MECHANISMS

MELANOCYTE MALIGNANT TRANSFORMATION AND MELANOMA PROGRESSION: The role of cellular stress and epigenetic mechanisms 

Temos investigado o papel de alterações epigenéticas, incluindo metilação de DNA, modificações em histonas e RNAs não codificantes, na relação entre condições sustentadas de estresse e transformação maligna, especialmente em melanócitos. Níveis aumentados de espécies reativas de oxigênio (ROS), causados por exemplo por inflamação crônica, envelhecimento e radiação ultravioleta, podem ser responsáveis pelo estabelecimento de marcas epigenéticas anormais e, com isso, contribuir com a transformação maligna. Utilizando modelos celulares murinos e humanos compreendendo linhagens celulares que correspondem a etapas distintas da progressão tumoral (modelos estabelecidos em nosso laboratório), temos como objetivo integrar dados em larga escala para desvendar alterações moleculares envolvidas tanto na aquisição do fenótipo maligno quanto de características agressivas. Desta forma, o estudo da relação entre estresse sustentado, marcas epigenéticas aberrantes e transformação maligna pode contribuir com um melhor entendimento de mecanismos envolvidos na gênese do melanoma e, com isso, abrir caminhos para o desenvolvimento de novas estratégias terapêuticas.

Professor responsável: Miriam Galvonas Jasiulionis

NUCLEAR RECEPTORS, INNATE IMMUNITY AND INFLAMMATORY MEDIATORS IN REPRODUCTIVE TISSUES AND THE CENTRAL NERVOUS SYSTEM: EMPHASIS IN ANDROLOGY

NUCLEAR RECEPTORS, INNATE IMMUNITY AND INFLAMMATORY MEDIATORS IN REPRODUCTIVE TISSUES AND THE CENTRAL NERVOUS SYSTEM: EMPHASIS IN ANDROLOGY

The scientific research developed by the group is inserted in the area of ​​molecular, endocrine and reproduction pharmacology, with the field of andrology as a convergent focus for the translation of the knowledge generated. The studies, carried out with national and international collaborators, aim to better understand the physiopharmacology of nuclear receptors for steroid hormones (androgens/AR and glucocorticoids/GR) and the role of innate immunity components (emphasis on beta-defensins) and inflammatory mediators in tissues reproductive (focus on the epididymis) and on the central nervous system. It also seeks to identify how these parameters act as “alert” signals to recognize tissue damage of an inflammatory nature (infectious or non-infectious) that, if not controlled, can lead to acute and chronic inflammation. More recently, the role of thyroedoxin-like chaperone proteins has also been investigated in epididymal biology. Using different experimental models in vivo, in vitro and ex-vivo (organotypic culture) in rodents, the following topics have been investigated: 1) study of nuclear receptor signaling (AR and GR) in the morphogenesis of the mesonephric duct (embryonic precursor of the epididymis ) and in the postnatal development of the epididymis of rats; 2) identification of the role and regulation of the expression of innate immunity effectors (β-defensins) in the morphogenesis of the mesonephric duct of rats; 3) study of the pathophysiological events of acute epididymitis caused by inflammatory stimulation (bacterial components) and their impact on fertility parameters, using an experimental epididymitis model that mimics the clinical condition; 4) identification of the role and regulation of the expression of innate immunity effectors (β-defensins) in the central nervous system and in the reproductive tract (focus on the epididymis) from adult mice submitted to the experimental model of social isolation that mimics the clinical condition of post-traumatic stress disorder: 5) study of the role and regulation of the expression of innate immunity effectors (β-defensins) in neuroinflammation installed with natural or accelerated aging in mice; 6) identification of the relationship between sex hormones and the role of protein disulfide isomerase in morphogenesis, postnatal development and epididymal function. The evaluation of multiomics data to discover relationships between nuclear receptor, gene and tissue signaling and relationships with human disease has also been used to support ongoing studies.

Professor: Maria Christina Werneck de Avellar

CALCIUM SIGNALING, CELL DEATH AND AUTOPHAGY MECHANISMS

CALCIUM SIGNALING, CELL DEATH AND AUTOPHAGY MECHANISMS

Cell death and autophagy are important processes of cells in different biological systems. The modulation of the mechanisms involved in autophagy can contribute to the modulation of cell death, aging and neurodegenerative processes. In our Laboratory we have been studying the processes of intracellular signaling and modulation of autophagy and cell death in neurodegenerative diseases. In the face of an aging population and an increase in progressive disorders related to the degeneration of the central nervous system, there is an increasing relevance in studing Parkinson's disease (PD). This understanding becomes essential to assist in the identification of targets for the development of new drugs or treatment strategies.

In our Laboratory, we aim to investigate the processes related to autophagy and its possible neuroprotective role in several diseases related to aging, including PD. We have been studying cell signaling and the involvement of ± -synuclein protein aggregates (Lewy bodies, the main pathological marker of PD), which can reduce autophagy, worsening PD-related neurodegenerative processes. We have also sought to study cellular processes and new pharmacological agents that can induce autophagy and evoke neuroprotective mechanisms.

We are now supported by FAPESP with a 5-year financing project for the study of cannabinoid substances obtained from a library of 44 compounds. The project has been carried out in in vivo, in vitro models and it will be performed in preclinical and clinical studies. In this way, translational science will be carried out in patients with PD, as cannabidiol and other cannabinoids may have pro-autophagic potential and reduce PD-related effects and behavior. This is a new frontier of knowledge and action, in the face of neurodegenerative diseases related to aging such as PD.

Professor: Soraya Soubhi Smaili

SYNAPTIC TRANSMISSION AND CELL SIGNALING

SYNAPTIC TRANSMISSION AND CELL SIGNALING

The intracellular cyclic AMP (cAMP) regulates several processes including contraction, metabolism, protein expression and function of striated and smooth muscle. Previous studies from our lab have shown that the increment in cAMP production in skeletal muscle induced by activation of stimulatory (Gs) protein coupled receptor (GsPCR) or adenylyl cyclase is followed by efflux of this cyclic nucleotide (Godinho & Costa-Jr, 2003). Once outside the cell, cAMP modulates skeletal muscle contraction via its metabolite adenosine, generated by sequential action of ecto-phosphodiesterases and ecto-5'-nucleotidases (Chiavegatti et al., 2008). Our results also showed the contracting effects of extracellular cAMP on tracheal smooth muscle (Pacini et al., 2018) which may affect the bronchodilator responses to inhaled β2-agonists, the actual focus of our research.

Professor: Rosely Oliveira Godinho

INFLUENCE OF INFLAMMASOMES IN INFLAMMATORY AND INFECTIOUS DISEASES

INFLUENCE OF INFLAMMASOMES IN INFLAMMATORY AND INFECTIOUS DISEASES

Inflammasomes are multiprotein platforms activated by a serie of molecular patterns from pathogens (PAMPs) or cell damage (DAMPS) and cytosolic disturbances. These platforms are responsible for the activation of inflammatory caspases 1/11 culminating in the secretion of IL-1b, IL-18 and the induction of pyroptosis. In addition to these conventional effector mechanisms, our group has been focused in the understanding of novel effector mechanisms mediated by inflammasomes and their consequences to the control of infections and physiopathology of inflammatory diseases.

Professor: Karina Ramalho Bortoluci

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