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Drug Discovery Today. Disease Models

Yoram Vodovotz
Properly-regulated inflammation is central to homeostasis. Traumatic injury, hemorrhagic shock, septic shock, and other injury-related processes such as wound healing are associated with dysregulated inflammation. Like many biological processes, inflammation is a dynamic, complex system whose function, like that of an analog clock, cannot be discerned simply from a laundry list of its parts (data). The advent of multiplexed platforms for gathering biological data, while providing an unprecedented level of detailed information about the inflammatory response, has paradoxically also proven to be overwhelming...
2016: Drug Discovery Today. Disease Models
Shane Lee, Wael F Asaad, Stephanie R Jones
Essential tremor (ET) is a neurological disorder of unknown etiology that is typically characterized by an involuntary periodic movement of the upper limbs. No longer considered monosymptomatic, ET patients often have additional motor and even cognitive impairments. Although there are several pharmacological treatments, no drugs have been developed specifically for ET [1], and 30-70% of patients are medication-refractory [2]. A subset of medication-refractory patients may benefit from electrical deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM), which receives cerebellar inputs...
2016: Drug Discovery Today. Disease Models
William W Lytton
Analysis of the brain as a dynamical system can assist drug development for dynamical diseases such as epilepsy. The pathological trajectories that make up a seizure differ significantly from the physiological trajectories of normal brain function. These trajectories depend on parameters - conductances and time constants of ion channels and synapses - that can be modified by drugs. Drug development will benefit by taking account of the way in which multiple parameters - multiple drug targets - produce trajectory alterations...
2016: Drug Discovery Today. Disease Models
Samuel A Neymotin, Salvador Dura-Bernal, Herman Moreno, William W Lytton
Dystonia is a movement disorder that produces involuntary muscle contractions. Current pharmacological treatments are of limited efficacy. Dystonia, like epilepsy is a disorder involving excessive activty of motor areas including motor cortex and several causal gene mutations have been identified. In order to evaluate potential novel agents for multitarget therapy for dystonia, we have developed a computer model of cortex that includes some of the complex array of molecular interactions that, along with membrane ion channels, control cell excitability...
2016: Drug Discovery Today. Disease Models
Haroon Anwar
Many signaling pathways crucial for homeostatic regulation, synaptic plasticity, apoptosis and immune response depend on Ca2+ . Ca2+ dysregulation disrupts normal function of neurons and neuronal networks. This causes severe motor and cognitive disabilities. Understanding how Ca2+ dysregulation triggers disease onset and progression, and affects downstream processes, can help identify targets for treatments. Because of intermingling of molecular pathways, dissecting the role of individual mechanisms and establishing causality is very challenging...
2016: Drug Discovery Today. Disease Models
Warren D Anderson, Rajanikanth Vadigepalli
A central goal of pharmacological efforts to treat central nervous system (CNS) diseases is to develop systemic therapeutics that can restore CNS homeostasis. Achieving this goal requires a fundamental understanding of CNS function within the organismal context so as to leverage the mechanistic insights on the molecular basis of cellular and tissue functions towards novel drug target identification. The immune system constitutes a key link between the periphery and CNS, and many neurological disorders and neurodegenerative diseases are characterized by immune dysfunction...
2016: Drug Discovery Today. Disease Models
Adam J H Newton, William W Lytton
The occlusion of a blood vessel in the brain causes an ischemic stroke. Current treatment relies restoration of blood flow within 3 hours. Substantial research has focused on neuroprotection to spare compromised neural tissue and extend the treatment time window. Despite success with animal models and extensive associated clinical testing, there are still no therapies of this kind. Ischemic stroke is fundamentally a multiscale phenomenon where a cascade of changes triggered by loss of blood flow involves processes at spatial scales from molecular to centimeters with damage occurring in milliseconds to days and recovery into years...
2016: Drug Discovery Today. Disease Models
Weronika Barcik, Eva Untersmayr, Isabella Pali-Schöll, Liam O'Mahony, Remo Frei
The intestinal immune system is intimately connected with the vast array of microbes present within the gut and the diversity of food components that are consumed daily. The discovery of novel molecular mechanisms, which mediate host-microbe-nutrient communication, have highlighted the important roles played by microbes and dietary factors in influencing mucosal inflammatory and allergic responses. In this review, we summarize the recent important findings in this field, which are important for food allergy and particularly relevant to animal models of food allergy...
2015: 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
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