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Drug Discovery Today. Disease Models

Jennifer J Linderman, Denise E Kirschner
Tuberculosis (TB) is a global health problem responsible for ~2 million deaths per year. Current antibiotic treatments are lengthy and fraught with compliance and resistance issues. There is a crucial need for additional approaches to provide a cost-effective means of exploring the design space for potential therapies. We discuss the use of mathematical and computational models in virtual experiments and virtual clinical trials both to develop new hypotheses regarding the disease and to provide a cost-effective means of discovering new treatment strategies...
2015: Drug Discovery Today. Disease Models
Jason H T Bates, Bradford J Smith, Gilman B Allen
Managing acute respiratory distress syndrome (ARDS) invariably involves the administration of mechanical ventilation, the challenge being to avoid the iatrogenic sequellum known as ventilator-induced lung injury (VILI). Devising individualized ventilation strategies in ARDS requires that patient-specific lung physiology be taken into account, and this is greatly aided by the use of computational models of lung mechanical function that can be matched to physiological measurements made in a given patient. In this review, we discuss recent models that have the potential to serve as the basis for devising minimally injurious modes of mechanical ventilation in ARDS patients...
2015: Drug Discovery Today. Disease Models
Geoffrey Clapp, Doron Levy
Recently, there has been significant activity in the mathematical community, aimed at developing quantitative tools for studying leukemia and lymphoma. Mathematical models have been applied to evaluate existing therapies and to suggest novel therapies. This article reviews the recent contributions of mathematical modeling to leukemia and lymphoma research. These developments suggest that mathematical modeling has great potential in this field. Collaboration between mathematicians, clinicians, and experimentalists can significantly improve leukemia and lymphoma therapy...
2015: Drug Discovery Today. Disease Models
Jarred R Mondoñedo, John S McNeil, Samir D Amin, Jacob Herrmann, Brett A Simon, David W Kaczka
Status asthmaticus (SA) is a severe, refractory form of asthma that can result in rapid respiratory deterioration and death. Treatment of SA with inhaled anesthetics is a potentially life-saving therapy, but remarkably few data are available about its mechanism of action or optimal administration. In this paper, we will review the clinical use of inhaled anesthetics for treatment of SA, the potential mechanisms by which they dilate constricted airways, and the side effects associated with their administration...
2015: Drug Discovery Today. Disease Models
Graham M Donovan, Merryn H Tawhai
Understanding and treatment of asthma is significantly complicated by the heterogeneous spectrum of phenotypes associated with the disease. Recent advances in phenotype classification promise more targeted therapies, but these categories are based on constellations of largely external measurements and are not necessarily indicative of underlying pathophysiology. We propose that computational modelling is a valuable tool that allows the disease spectrum to be decomposed not into phenotypes but rather into groups organized by underlying dysfunction, referred to by some authors as endotypes...
2015: Drug Discovery Today. Disease Models
Tilo Winkler, Jose G Venegas, R Scott Harris
Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poor ventilation (ventilation defects, VDefs) in the lungs. The emphasis of this review is on mathematical modeling of the mechanisms involved in bronchoconstriction and the emergence of the complex airway behavior that leads to VDefs...
2015: Drug Discovery Today. Disease Models
Béla Suki, Harikrishnan Parameswaran
Emphysema is a progressive disease characterized by deterioration of alveolar structure and decline in lung function. While morphometric and molecular biology studies have not fully uncovered the underlying mechanisms, they have produced data to advance computational modeling. In this review, we discuss examples in which modeling has led to novel insight into mechanisms related to disease progression. Finally, we propose a general scheme of multiscale modeling approach that could help unravel the progressive nature of emphysema and provide patient specific mechanisms perhaps suitable for use in treatment therapies...
July 8, 2014: Drug Discovery Today. Disease Models
Nic Smith, Natalia Trayanova
No abstract text is available yet for this article.
2014: Drug Discovery Today. Disease Models
Pau Medrano-Gracia, Brett R Cowan, Avan Suinesiaputra, Alistair A Young
Heart shape and function are major determinants of disease severity and predictors of future morbidity and mortality. Many studies now rely on non-invasive cardiac imaging techniques to quantify structural and functional changes. Statistical anatomical modeling of heart shape and motion provides a new tool for the quantification and evaluation of heart disease. This review surveys recent progress in the evaluation of statistical shape measures across populations and sub-cohorts, and highlights collaborative efforts to facilitate data sharing and atlas-based shape analysis...
2014: Drug Discovery Today. Disease Models
Vladimir Yarov-Yarovoy, Toby W Allen, Colleen E Clancy
A wealth of experimental data exists describing the elementary building blocks of complex physiological systems. However, it is increasingly apparent in the biomedical sciences that mechanisms of biological function cannot be observed or readily predicted via study of constituent elements alone. This is especially clear in the longstanding failures in prediction of effects of drug treatment for heart rhythm disturbances. These failures stem in part from classical assumptions that have been made in cardiac antiarrhythmic drug development - that a drug operates by one mechanism via one target receptor that arises from one gene...
2014: Drug Discovery Today. Disease Models
Beom Jin Lim, Hai-Chun Yang, Agnes B Fogo
Current medical therapies may delay chronic kidney disease progression. However, increasing experimental evidence indicates remission or even regression can be achieved. In order to study mechanisms progression vs. regression by different interventions, appropriate animal models and research design must be implemented. We review key information of selected models, including etiology, pathogenesis, procedure, time course and assessment of potential regression.
2014: Drug Discovery Today. Disease Models
Tracy L McGaha, Michael P Madaio
Nephritis as a result of autoimmunity is a common morbidity associated with Systemic Lupus Erythematosus (SLE). There is substantial clinical and industry interest in medicinal intervention in the SLE nephritic process; however, clinical trials to specifically treat lupus nephritis have not resulted in complete and sustained remission in all patients. Multiple mouse models have been used to investigate the pathologic interactions between autoimmune reactivity and SLE pathology. While several models bear a remarkable similarity to SLE-driven nephritis, there are limitations for each that can make the task of choosing the appropriate model for a particular aspect of SLE pathology challenging...
2014: Drug Discovery Today. Disease Models
Hitoshi Suzuki, Yusuke Suzuki, Jan Novak, Yasuhiko Tomino
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. IgAN is characterized by the mesangial accumulation of immune complexes containing IgA1, usually with co-deposits of complement C3 and variable IgG and/or IgM. Although more than 40 years have passed since IgAN was first described, the mechanisms underlying the disease development are not fully understood. Small-animal experimental models of IgAN can be very helpful in studies of IgAN, but development of these models has been hindered by the fact that only humans and hominoid primates have IgA1 subclass...
2014: Drug Discovery Today. Disease Models
Andrew J Rennekamp, Randall T Peterson
Small molecules screens conducted with living zebrafish have become a commonly practiced technique for small molecule discovery. Embryonic and larval zebrafish exhibit an almost limitless range of phenotypes, from the cellular to the organismal. Consequently, small molecule screens can be designed to discover compounds modifying any of these phenotypes. The compounds discovered by zebrafish screens pose unique challenges for target identification, but the zebrafish also provides several powerful approaches for identifying targets and determining mechanisms of action...
2013: Drug Discovery Today. Disease Models
Christian L Lino Cardenas, Naftali Kaminski, Daniel J Kass
MicroRNAs are implicated in many biological and pathological processes and are emerging as key actors in lung health and disease. Specific patterns of dysregulated microRNAs have been found in idiopathic pulmonary fibrosis (IPF), an untreatable interstitial lung disease of unknown etiology. IPF is characterized by dramatic and extensive phenotypic changes in the lung that include alveolar cell hyperplasia, fibroblast proliferation and formation of myofibroblast foci, deposition of extracellular matrix, and changes in lung transcriptional programming...
2013: Drug Discovery Today. Disease Models
Lama Noureddine, Sachin Hajarnis, Vishal Patel
Polycystic kidney disease (PKD), the most common genetic cause of chronic renal failure, is characterized by the presence of numerous fluid-filled cysts in renal parenchyma. Despite recent progress, no FDA-approved therapy is available to retard cyst growth. Here, we review current evidence implicating two groups of miRNAs - the miR-17~92 cluster and miR-200s - in the pathogenesis of PKD. We present a new hypothesis for cyst growth involving miRNAs and regulation of PKD gene dosage. We propose that manipulating miRNA function in an attempt to normalize PKD gene dosage represents a novel therapeutic strategy in PKD...
2013: Drug Discovery Today. Disease Models
Akiko Maeda, Krzysztof Palczewski
Continuous generation of visual chromophore through the visual (retinoid) cycle is essential to maintain eyesight and retinal heath. Impairments in this cycle and related pathways adversely affect vision. In this review, we summarize the chemical reactions of vitamin A metabolites involved in the retinoid cycle and describe animal models of associated human diseases. Development of potential therapies for retinal disorders in these animal models is also introduced.
2013: Drug Discovery Today. Disease Models
Jeremy S Duffield, Monica Grafals, Didier Portilla
Chronic disease of the kidneys has reached epidemic proportions in industrialized nations. New therapies are urgently sought. Using a combination of animal models of kidney disease and human biopsy samples, a pattern of dysregulated microRNA expression has emerged which is common to chronic diseases. A number of these dysregulated microRNA have recently been shown to have functional consequences for the disease process and therefore may be potential therapeutic targets. We highlight microRNA-21, the most comprehensively studied microRNA in the kidney so far...
2013: Drug Discovery Today. Disease Models
Sara E Pinney
Intrauterine growth retardation has been linked to the development of type 2 diabetes later in life and the mechanisms underlying this phenomena are unknown. Epidemiological studies in humans show a distinct link with the exposure to an intrauterine insult that results in low birth weight and the development of type 2 diabetes in adulthood. Intrauterine growth retardation can be induced in rodent models by exposing the pregnant rat to a low protein diet, total calorie restriction, high dose glucocorticoids or inducing uteroplacental insufficiency, all which result in abnormalities in glucose homeostasis in the offspring later in life...
2013: Drug Discovery Today. Disease Models
Randall T Peterson, Calum A Macrae
As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward...
2013: Drug Discovery Today. Disease Models
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