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Doença: Aspergilose Pulmonar Invasiva (IPA)
• Aspergillus fumigatus é um fungo saprófito encontrado no solo. Cresce em vegetação em decomposição de latitudes temperadas subtropicais e quentes;
• Os seres humanos inalam centenas de conídios (esporos) de A. fumigatus conidia diariamente;
• Existem mais de 200.000 casos de aspergilose documentados anualmente;
• As infecções humanas causadas por A. fumigatus podem variar de doenças alérgicas a aspergilose invasiva, dependendo do estado imunológico do hospedeiro;
• Existem três classes de antifúngicos para o tratamento da aspergilose: azóis e polienos direcionados ao ergosterol e equinocandinas visando a síntese de β-1,3 glucano;
• O primeiro caso de resistência a azol foi relatado em 1989.
Modelo: Aspergillus fumigatus
Disease: Neuropsychiatric disorders
• Psychiatric disorders may affect up to 20% of the world's population;
• In order to depict and propose biochemical pathways and biological processes associated with psychiatric disorders, pre-clinical models must be established;
• While animal models are normally used in biomedical research, these may be challenging to establish for psychiatric studies, considering the intrinsic characteristics of psychiatric disorders;
• Postmortem brain tissue may be also useful, but limited to address questions regarding diagnostic and treatment testing;
• In this scenario, in vitro models may be therefore useful;
• The development of human-induced pluripotent stem cells (iPSCs) may provide human neuronal-like tissue;
• iPSCs can recapitulate the phenotype of the donor also affords the possibility of using this approach to study both the disease and control states in a given medical area.
Model: Astrocytes, Oligodendrocytes and Neurons
Disease: Frailty and age-related diseases
• Caenorhabditis elegans is a free-living nematode with approximately 1 mm, which is widely used in the literature as a model organism for aging and age-related diseases;
• Caenorhabditis elegans lives about 3 weeks in nematode growth medium while feeding bacteria. The medium can be supplemented with compounds and bacteria can also be manipulated, making C. elegans a good model to study pharmacology, toxicology, innate immunity and microbiome-host interaction;
• Worms are highly amenable to genetic manipulation, making them a powerful tool to study the genetics of aging and disease;
• There is wide evolutionary conservation between worms and humans. Indeed, most pathways involved in aging are conserved between the two species;
• Among the conserved pathways, it is worth mentioning lipid metabolism, which makes C. elegans also a good model to study fat accumulation.
Model: C. elegans stained with Oil Red O for lipid quantification
Disease: Lipodystrophy
• Lipodystrophy occurs when there is a defect in the ability of adipose tissue to accumulate fat;
• Lipodystrophy may be congenital or acquired, being a common cause of lipodystrophy the chronic use of antiretroviral drugs (e.g., by HIV patients);
• Lipodystrophy causes insulin resistance, cardiovascular disease and premature aging;
• Fat-specific knockout of the enzyme DICER in mice resembles many features of human partial lipodystrophy;
• Fat-specific DICER knockout (AdicerKO) mice are insulin resistant, dyslipidemic, and exhibit a premature risk of mortality.
Model: High fat diet-fed AdicerKO (right) versus wild type (left) mice (Mori et al., 2014. JCI)
Disease: Intestinal infection by Clostridioides difficile
• Clostridioides difficile formerly known as Clostridium difficile is sporulated bacteria that cause intestinal infection;
• Intestinal infection by C.difficile is associated with the use of oral antibiotics such as clindamycin and cephalosporins. Other risk factors for this infection include age and immune suppression;
• C.difficile infects the colon and causes diarrhea, abdominal pain and inflammation of the tissue. These signs and symptoms are caused by toxins produced by C.difficile which cause destruction of intestinal barrier and accumulation of leukocytes in the colon;
• Infection by this bacterium results in a wide spectrum of clinical conditions, including an asymptomatic state, mild and self-limited diarrhea, pseudomembranous colitis and fulminant colitis;
• This murine model mimics clinical aspects of the human disease including presence of diarrhea, leukocyte infiltration, barrier damage and colitis.
Model: murine model of Clostridium difficile-associated disease (Chen et al., 2008. Gastroenterology)
Disease: Periodontitis
• Periodontitis is a highly prevalent chronic inflammatory disease that affects the tissue that supports the tooth;
• The etiology of this disease is complex and involves changes in the composition of microbiota and the presence of certain types of bacteria such as P. gingivalis or A. actinomycetemcomitans; host factors that regulate for example the activation/control of immune/inflammatory responses and environmental factors that modify host response such as use of certain types of drugs and presence of diseases such as diabetes.
• The murine model of periodontitis recapitulates some of clinical aspects of the human disease including leukocyte infiltration to the gingiva and alveolar bone loss.
Model: Ligature-induced periodontitis in mice (Abe & Hagishengallis, J Immunol Methods. 2013)
Disease: Obesity and type 2 diabetes.
• Obesity is the major risk factor for insulin resistance and metabolic syndrome;
• Obesity-induced inflammation induces insulin resistance;
• Obesity induces adipose tissue macrophage accumulation and activation;
• Obesity is associated with elevated levels of leptin and leptin resistance;
• Leptin deficiency or leptin receptor deficiency induces obesity and the subsequent Adipose tissue inflammation and insulin resistance.
Model: High fat diet-induced obesity; leptin and leptin receptor deficiency (Moraes-Vieira P et al. Cell Metabolism, 2014; Moraes-Vieira et al. Diabetes, 2016)
Disease: Infectious diseases
• Infectious diseases are a serious problem worldwide;
• Parasitic diseases, such as Leishmaniasis are epidemic in tropical countries with no effective treatment or vaccine;
• Many human illnesses are due to infections with either bacteria or viruses;
• Most bacteria diseases can be treated with antibiotics, but antibiotic resistance is becoming a serious problem;
• Pathogens such as parasites, bacteria and virus are sensed by the innate immune system and triggers an inflammatory response;
• Endemic and emerging viruses are important human pandemic threats;
• Infectious models are important tools to understand the pathophysiology of several infectious diseases.
Model: animal models to study infectious diseases
Disease: Autoimmune Diseases
• It is estimated that the worldwide prevalence of autoimmune diseases is around 8%;
• However, the vast majority of autoimmune diseases still have an unknown etiology;
• Autoimmune diseases are among the main causes of mortality in women up to 65 yo;
• The incidence of autoimmune diseases has increased in recent decades;
• Autoimmune diseases represent a major socioeconomic problem, since they mainly affect young adults in the most productive phase of life.
Model: Experimental Autoimmune Encephalomeylitis
