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Genetic Studies of the Etiology of Asthma

Barnes, Kathleen C.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
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726.655%
Asthma is a heterogeneous disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyper-responsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes. A considerable proportion of asthma is IgE-mediated, but the observation that not all individuals with asthma are atopic adds to the heterogeneity. Although a genetic basis for asthma is undeniable, elucidation of polymorphisms that are “causal” is greatly hampered by variability in the clinical phenotype, which is likely due to the multiple molecular mechanisms underlying the complex pathological processes involved in disease development and progression. One objective of this review is to consider progress that has been made to date in gene discovery in the field of asthma, with a focus on the evolution of molecular genetic methods that have led to the discoveries thus far, and with a particular focus on the major advances owed to the published genome-wide association studies (GWAS) on asthma to date. A second objective is to consider a Darwinian approach toward understanding the genetic underpinnings of asthma...

Genetics of Complex Airway Disease

Cookson, William O. C.; Moffatt, Miriam F.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
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727.2052%
The past 3 years have seen highly significant genetic effects identified for a wide variety of common complex diseases, including the airway disorders of asthma and chronic obstructive pulmonary disease. It appears that only a portion of the genetically mediated susceptibility to complex diseases has been identified, and there is much left to be discovered. This review briefly describes the results of the genome-wide association studies of asthma and gives an overview of the parallel and increasingly large-scale studies that are taking place with chronic obstructive pulmonary disease. The future impact is discussed of technological advances that allow increasingly large-scale gene expression studies, next-generation sequencing, and genome-wide testing for epigenetic effects. The use of genetic technology to examine the airway microbiota that interact with the mucosa in health and disease is described.

Pulmonary Arterial Hypertension: Insights from Genetic Studies

Loyd, James E.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
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625.62344%
Familial pulmonary arterial hypertension (FPAH) was described 60 years ago, but real progress in understanding its origins and pathogenesis is just beginning. Germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) are responsible for the disease in most families, and also in many sporadic cases of idiopathic PAH. Heritable PAH refers to patients with a positive family history, or with a responsible genetic mutation, and is an autosomal dominant disease that affects females disproportionately, may occur at any age, and is characterized by reduced penetrance and variable expressivity. These characteristics suggest that other endogenous or exogenous factors modify its expression. Several different factors have recently been demonstrated to modify the clinical expression of BMPR2 mutation, including estrogen metabolites and functional polymorphisms in transforming growth factor–β1 and CYP1B1. Furthermore, a linkage study recently identified modifier loci for BMPR2 clinical expression, which suggests an oligogenic model. Clinical testing for BMPR2 mutations is available for families with heritable and idiopathic PAH, and is an evolving model of personalized medicine. Variable age of onset and decreased penetrance confound genetic counseling...

Idiopathic Pulmonary Fibrosis: Update on Genetic Discoveries

Garcia, Christine Kim
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
625.12133%
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lungs that increases in prevalence with advanced age. Recent evidence indicates that mutations in genes of two different biologic pathways lead to the common phenotype of familial pulmonary fibrosis (FPF) and sporadic IPF. Mutations in the genes encoding the lung surfactant proteins C and A2 (SFTPC and SFTPA2, respectively) cause increased endoplasmic reticulum stress in type II alveolar epithelial cells. Mutations in the genes encoding telomerase (TERT and TERC) cause IPF through shortening of telomere lengths and probable exhaustion of lung stem cells. All of the mutations are individually rare, but, collectively, TERT mutations are the most common genetic defect found in FPF. The overall penetrance of pulmonary fibrosis in TERT mutation carriers is 40% in subjects with a mean age of 51 years. Penetrance increases with advanced age, is greater in males than in females, and is positively associated with fibrogenic environmental exposures. Short telomere lengths are found in patients with FPF and sporadic IPF without mutations in telomerase, suggesting that the biologic pathway of telomerase dysfunction provides a biologic explanation for the age-related prevalence of IPF. The molecular data of two seemingly unrelated biologic pathways—alveolar epithelial endoplasmic reticulum stress and telomerase dysfunction—are beginning to elucidate the pathogenesis of IPF. These results have potentially predictive and therapeutic value.

Toward a Systematic Understanding of mRNA 3′ Untranslated Regions

Zhao, Wenxue; Blagev, Denitza; Pollack, Joshua L.; Erle, David J.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
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827.0289%
Messenger RNAs (mRNAs) contain prominent untranslated regions (UTRs) that are increasingly recognized to play roles in mRNA processing, transport, stability, and translation. 3′ UTRs are believed to harbor recognition sites for a diverse set of RNA-binding proteins that regulate gene expression as well as most active microRNA target sites. Although the roles of 3′ UTRs in the normal and diseased lung have not yet been studied extensively, available evidence suggests important roles for 3′ UTRs in lung development, inflammation, asthma, pulmonary fibrosis, and cancer. Systematic, genome-wide approaches are beginning to catalog functional elements within 3′ UTRs and identify the proteins and microRNAs that interact with these elements. Application of new data sets and experimental approaches should provide powerful insights into how 3′ UTR-mediated regulatory events contribute to disease and may inspire novel therapeutic approaches.

Genomic Investigations into Acute Inflammatory Lung Injury

Garcia, Joe G. N.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
2123.5069%
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are complex illnesses involving the interplay of both environmental (such as mechanical ventilation) and genetic factors. To understand better the underlying mechanisms of pathogenesis associated with ALI, we recently identified several candidate genes by global expression profiling in preclinical models of ALI and relevant single-nucleotide polymorphisms. We summarize here several strategies successfully used to identify novel ALI candidate genes and detail the validation of variants in these genes as contributing factors to ALI pathobiology, conclusions based on functional analyses, and specific genetic association studies conducted in ALI cohorts. Continued insights into ALI pathogenesis and identification of genetic variants, which confer ALI risk and severity, promise to reveal novel molecular therapeutic targets that can be translated into personalized treatments to reduce the very high, unacceptable mortality of this disorder.

Pathway-Based Classification of Lung Cancer: A Strategy to Guide Therapeutic Selection

Nevins, Joseph R.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
734.6455%
The critical challenge in virtually all cancer research is heterogeneity: “Breast cancer” and “lung cancer” are actually collections of disease with distinct molecular mechanisms and clinical characteristics. The challenge is evident in the complexity of most cancers with multiple mutations and alterations generating the cancer phenotype, requiring therapeutic strategies that can match the complexity with equally complex combination regimens. Substantial progress in treatment requires major advances in methods to define refined, “common mechanism” subgroups to allow development of combination therapeutics that target these individual mechanisms. Our work is on the use of genomic signatures of oncogenic signaling pathways that provide an opportunity to dissect the complexity of lung cancer and to serve as tools to direct the use of targeted therapeutic agents.

Advances in Proteomic Strategies toward the Early Detection of Lung Cancer

Hassanein, Mohamed; Rahman, Jamshedur S. M.; Chaurand, Pierre; Massion, Pierre P.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
740.5765%
Since the advent of the new proteomics era more than a decade ago, large-scale studies of protein profiling have been exploited to identify the distinctive molecular signatures in a wide array of biological systems spanning areas of basic biological research, various disease states, and biomarker discovery directed toward therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomics approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures specific for invasive lung cancer and preinvasive lesions have begun to emerge. In this review we provide a critical assessment of the state of recent advances in proteomic approaches and the biological lessons they have yielded, with specific emphasis on the discovery of biomarker signatures for the early detection of lung cancer.

Proteostasis: A New Therapeutic Paradigm for Pulmonary Disease

Bouchecareilh, Marion; Balch, William E.
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
638.4958%
Among lung pathologies, α1AT, chronic obstructive pulmonary disease (COPD), emphysema, and asthma are diseases triggered by local environmental stress in the airway that we refer to herein collectively as airway stress diseases (ASDs). A deficiency of α-1-antitrypsin (α1AT) is an inherited genetic disorder that is a consequence of the misfolding of α1AT during protein synthesis in liver hepatocytes, reducing secretion to the plasma and delivery to the lung. Deficiency of α1AT in the lung triggers a similar pathological phenotype to other ASDs. Moreover, the loss of α1AT in the lung is a well-known environmental risk factor for COPD/emphysema. To date there are no effective therapeutic approaches to address ASDs, which reflects a general lack of understanding of their cellular basis. Herein, we propose that ASDs are disorders of proteostasis. That is, they are initiated and propagated by a common theme—a challenge to protein folding capacity maintained by the proteostasis network (PN) (see Balch et al., Science 2008;319:916–919). The PN is a network of chaperones and degradative components that generates and manages protein folding pathways responsible for normal human physiology. In ASD, we suggest that the PN system fails to respond to the increased burden of unfolded proteins due to genetic and environmental stresses...

Transcriptomic Studies of the Airway Field of Injury Associated with Smoking-Related Lung Disease

Gower, Adam C.; Steiling, Katrina; Brothers, John F.; Lenburg, Marc E.; Spira, Avrum
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
741.0571%
The “field of injury” hypothesis proposes that exposure to an inhaled insult such as cigarette smoke elicits a common molecular response throughout the respiratory tract. This response can therefore be quantified in any airway tissue, including readily accessible epithelial cells in the bronchus, nose, and mouth. High-throughput technologies, such as whole-genome gene expression microarrays, can be employed to catalog the physiological consequences of such exposures in the airway epithelium. Pulmonary diseases such as chronic obstructive pulmonary disease, lung cancer, and asthma are also thought to be associated with a field of injury, and in patients with these diseases, airway epithelial cells can be a useful surrogate for diseased tissue that is often difficult to obtain. Global measurement of mRNA and microRNA expression in these cells can provide useful information about the molecular pathogenesis of such diseases and may be useful for diagnosis and for predicting prognosis and response to therapy. In this review, our aim is to summarize the history and state of the art of such “transcriptomic” studies in the human airway epithelium, especially in smoking and smoking-related lung diseases, and to highlight future directions for this field.

Aspen Lung Conference 2010: Systems Biology of Lung Diseases—Progress in the Omics Era

Sheppard, Dean
Fonte: American Thoracic Society Publicador: American Thoracic Society
Tipo: Artigo de Revista Científica
Publicado em 01/05/2011 EN
Relevância na Pesquisa
967.4716%
The 53rd annual Thomas L. Petty Aspen Lung Conference focused on the dramatic progress that has been made in the past several years in applying large-scale, unbiased data acquisition (“omics”) to the study of lung biology and disease. The conference organizers, Mark Geraci, Ivor Douglas, Stephen Rennard, and David Schwartz, put together a terrific program, and the invited speakers and participants presented data describing the rapid evolution of experimental approaches that should encourage pulmonary scientists to begin to think about a true molecular systems biology of the lung.