Drug Discovery Today: Disease Models最新文献

Lesch–Nyhan Disease (LND) is a rare X-linked recessive metabolic and neurological syndrome due to the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Peculiar neurological symptoms occur in LND: dystonia, choreoathetosis, compulsive self-injurious behaviour, with no obvious correlation to the deficiency of this purine salvage anzyme. A dopaminergic deficit was found to underlie the neurologic symptoms, but the aetiology for such alteration seemed inexplicable. Several lines of research were carried out to find the molecular basis for the neurological phenotype, and HPRT deficient animal and cellular models were developed. None of them, animal or cellular model, can be considered the completely proper one. Available animal models are rodents, which share several biochemical and molecular abnormalities with HPRT deficient patients, but do not display similar neurologic symptoms. Cellular models obtained from different cell lines present notable biochemical and molecular aberrations though many discrepancies suggest significant differences depending upon cell types and tissue source. Nevertheless, experimental studies on both models provided remarkable information on the biochemical and molecular pathways potentially responsible for the neurological damage in this disease, demonstrating transcriptional aberrations affecting different genes in various metabolic pathways and gene dysregulations in neuronal development and differentiation, producing neurotransmission defects. These findings led to attribute an unexpected paramount role in neurodevelopment to HPRT, beside the well-known metabolic functions.

Cerebral cavernous malformation (CCM) is a rare disease of genetic origin characterized by dilated and leaky capillaries occurring mainly in the central nervous system. CCM can arise sporadically or may be inherited as an autosomal dominant condition with incomplete penetrance and variable clinical expressivity. The sporadic form accounts for up to 80% of cases, whereas the familial form accounts for at least 20% of cases. Genetic studies have identified three genes associated with CCMs: KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3).

Recently, great advances in understanding the pathophysiology of CCM disease have been obtained thanks to the use of animal and cellular models displaying all or some of the pathological characteristics that are observed in the human disease. Despite interspecies differences and the difficulty in creating animal models that completely recapitulate the human CCM disease onset and progression, these models have been helpful in identifying new molecular mechanisms underlying CCM development and in testing novel pharmacological therapies.

Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the homogentisate 1,2-dioxygenase (HGD) enzyme is deficient, causing an elevation of its substrate homogentisic acid (HGA). Overtime, elevated HGA causes connective tissue ochronosis, leading to a severe and early onset osteoarthropathy. The use of HGD deficient mouse models in this metabolic bone disease have provided the opportunity to investigate AKU pathophysiology and potential treatments. An ENU mutagenesis AKU mouse model (BALB/c Hgd^−/−) provided the means to explore the onset of pigmentation in cartilage and treatment of AKU with nitisinone, an inhibitor of the upstream enzyme forming HGA. This work provided evidence that nitisinone could not only lower circulating HGA, but could also prevent ochronosis and halt disease progression, leading to its off-label use at the National Alkaptonuria Centre (Liverpool, UK) and its subsequent testing in human clinical trials (DevelopAKUre). Recently, a new targeted AKU mouse model (Hgd tm1a^−/−, C57BL/6) has been established, offering a LacZ reporter gene for localising gene expression and LoxP and FRT sites that enabled generation of an inducible and liver-specific HGD knockout model (Hgd tm1d MxCre^+/−). This conditional model determined the importance of the liver as a target organ for future gene/enzyme replacement therapies in AKU. The contribution of AKU mouse models has clearly accelerated the treatment and knowledge of this rare disease, and will continue to be used.

Mice are frequently used in experimental models of respiratory diseases due to their ease of manipulation, genetic homogeneity within inbred populations, and possibility of standardizing environmental exposures. However, it is well established that genetic strain variations in mice may exist, which imply changes in extracellular matrix (ECM) composition and degree of ECM remodeling, with potential for major impacts on respiratory mechanics. The lung ECM is mainly composed of fibrous proteins (collagen and elastin), glycoproteins (fibronectin and laminin), proteoglycans (PGs), and glycosaminoglycans (GAGs). The functions of many ECM components are well described, but their role in the pathogenesis of respiratory diseases, such as emphysema and asthma, requires further elucidation. The aim of this review is to address ECM composition, function, and remodeling as well as demonstrate its relationship with the mechanical profile of the lung in different strains of mice subjected to experimental emphysema and allergic asthma.

Respiratory mechanics assessment in animal models of respiratory diseases is considered a reliable tool to understand how structural changes impact lung function. Mathematical models, such as the equation of motion and the constant-phase model are used to describe the properties of the respiratory system. The equation of motion is valued because it is relatively simple to apply and describes the respiratory systems with few parameters. The constant-phase model is more complex but provides more detailed information about different lung compartments. In this review, we summarize how respiratory mechanics have been used to describe lung behavior as well as how these measurements reflect the progression of structural changes caused by emphysema and asthma in animal models.

Breathing is achieved without thought despite being controlled by a complex neural network. The diaphragm is the predominant muscle responsible for force/pressure generation during breathing, but it is also involved in other non-ventilatory expulsive behaviors. This review considers alterations in diaphragm muscle fiber types and the neural control of the diaphragm across our lifespan and in various disease conditions.

The morphology of the mouse respiratory system has been studied in several different models of respiratory diseases, but quantitative morphological methods such as stereology are still only employed sporadically. This review discusses the use of stereology as a tool to understand the morphology of the mouse respiratory system and its link to the study of pulmonary mechanics. An integrated approach to study lung function in mice is being proposed, by combining non-invasive and invasive methods to analyze pulmonary mechanics, coupled with stereological investigations of lung morphology.

This mini-review aims to critically discuss the advantages and disadvantages of invasive versus noninvasive methods used to access pulmonary function especially in mice models of lung diseases. We briefly discussed the differences between both methods in handling expertise, number of mice required, length of time to determine lung function and anesthetic and/or use of muscle relaxant. Since noninvasive method received more criticisms than invasive method, we discussed critically the seminal studies that lend support to the disapproval of that method as measure of lung function. We show that the criticisms to the use of noninvasive method are biased or exaggerated and in general not hampered by experimental data obtained in several studies. Accordingly, in many studies the invasive method confirmed the results obtained with noninvasive method indicating that at practical level both methods were more coincident than discordant. Since both methods for measuring lung function have limitations and merits, we suggest that depending on focus of the study one method could be more adequate than the other. In studies where lung mechanical function is the main focus, the invasive method might be required. However, when determination of lung function is just one parameter among several others that characterizes lung disease, the noninvasive method might fit better since it allows performing longitudinal determinations of lung function followed by other lung pathologic parameters using smaller numbers of animals. Finally, in some studies the noninvasive method could be used to screen different experimental protocols and then the invasive method applied to confirm the positive results.

Lysosomal storage disorders are a group of genetic metabolic disorders caused by dysfunctional endosomal-lysosomal hydrolases, altered vesicular trafficking or biogenesis of the lysosome. This results in the accumulation of partially degraded substrates within cells, leading to abnormalities in multiple organ systems and reduced life expectancy. These diseases are chronic and progressive with the more severe cases experiencing the onset of disease symptoms early in life. These symptoms include skeletal, joint, airway and cardiac manifestations. Many of the lysosomal storage disorders exhibit significant respiratory issues, which frequently appear to affect pulmonary surfactant metabolism leading to an increased morbidity. Interstitial lung disease (ILD) refers to a group of disorders involving the airspaces and tissue compartments of the lung. The major categories of ILD in children that present in the neonatal period include developmental disorders, growth disorders, pulmonary surfactant dysfunction disorders, and specific conditions of unknown etiology unique to infancy. The purpose of this review is to examine the commonalities between lysosomal storage disorders with respiratory pathology and interstitial lung diseases. Increased awareness of the commonalities may instigate a more thorough investigation of symptoms thus providing an accurate and timely diagnosis enabling more precise treatment that will improve patient wellbeing.