RESUMEN
Recent discoveries indicate that disorders of protein folding and degradation play a particularly important role in the development of lung diseases and their associated complications. The overarching purpose of the National Heart, Lung, and Blood Institute workshop on "Malformed Protein Structure and Proteostasis in Lung Diseases" was to identify mechanistic and clinical research opportunities indicated by these recent discoveries in proteostasis science that will advance our molecular understanding of lung pathobiology and facilitate the development of new diagnostic and therapeutic strategies for the prevention and treatment of lung disease. The workshop's discussion focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for diagnosis and treatment.
Asunto(s)
Enfermedades Pulmonares/etiología , Deficiencias en la Proteostasis/etiología , Envejecimiento , Investigación Biomédica , Descubrimiento de Drogas , Educación , Humanos , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , National Heart, Lung, and Blood Institute (U.S.) , Pliegue de Proteína/efectos de los fármacos , Deficiencias en la Proteostasis/diagnóstico , Deficiencias en la Proteostasis/tratamiento farmacológico , Deficiencias en la Proteostasis/terapia , Estados UnidosRESUMEN
Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled "Future Research Directions in Early CF Lung Disease" on September 21-22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene-environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease.
Asunto(s)
Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Enfermedades Pulmonares/epidemiología , Investigación/tendencias , Distribución por Edad , Edad de Inicio , Niño , Desarrollo Infantil/fisiología , Preescolar , Fibrosis Quística/genética , Fibrosis Quística/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Progresión de la Enfermedad , Educación , Femenino , Predicción , Humanos , Lactante , Recién Nacido , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/fisiopatología , Masculino , Tamizaje Neonatal/métodos , Prevalencia , Pronóstico , Investigación/normas , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Estados UnidosRESUMEN
Genome-wide association studies (GWAS) have revealed novel genes and pathways involved in lung disease, many of which are potential targets for therapy. However, despite numerous successes, a large proportion of the genetic variance in disease risk remains unexplained, and the function of the associated genetic variations identified by GWAS and the mechanisms by which they alter individual risk for disease or pathogenesis are still largely unknown. The National Heart, Lung, and Blood Institute (NHLBI) convened a 2-day workshop to address these shortcomings and to make recommendations for future research areas that will move the scientific community beyond gene discovery. Topics of individual sessions ranged from data integration and systems genetics to functional validation of genetic variations in humans and model systems. There was broad consensus among the participants for five high-priority areas for future research, including the following: (1) integrated approaches to characterize the function of genetic variations, (2) studies on the role of environment and mechanisms of transcriptional and post-transcriptional regulation, (3) development of model systems to study gene function in complex biological systems, (4) comparative phenomic studies across lung diseases, and (5) training in and applications of bioinformatic approaches for comprehensive mining of existing data sets. Last, it was agreed that future research on lung diseases should integrate approaches across "-omic" technologies and to include ethnically/racially diverse populations in human studies of lung disease whenever possible.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedades Pulmonares/genética , Investigación Biomédica , Congresos como Asunto , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenotipo , Estados UnidosRESUMEN
Airway smooth muscle (ASM) plays a pivotal role in modulating bronchomotor tone but also orchestrates and perpetuates airway inflammation and remodeling. Despite substantial research, there remain important unanswered questions. In 2006, the National Heart, Lung, and Blood Institute sponsored a workshop to define new directions in ASM biology. Important questions concerning the key functions of ASM include the following: Does developmental dysregulation of ASM function promote airway disease, what key signaling pathways in ASM evoke airway hyperresponsiveness in vivo, do alterations in ASM mass affect excitation-contraction coupling, and can ASM modulate airway inflammation and remodeling in a physiologically relevant manner? This workshop identified critical issues in ASM biology to delineate areas for scientific investigation in the identification of new therapeutic and diagnostic approaches in asthma, chronic obstructive pulmonary disease, and cystic fibrosis.
Asunto(s)
Broncoconstricción/fisiología , Músculo Liso , Sistema Respiratorio , Actinas/fisiología , Broncoconstricción/inmunología , Humanos , Inflamación/fisiopatología , Músculo Liso/inmunología , Músculo Liso/fisiología , National Heart, Lung, and Blood Institute (U.S.) , Sistema Respiratorio/crecimiento & desarrollo , Sistema Respiratorio/inmunología , Sistema Respiratorio/fisiopatología , Estados UnidosRESUMEN
Cystic fibrosis (CF) is a genetic disease caused by autosomal recessive mutations of the CF transmembrane regulator, CFTR. CFTR functions in the plasma membrane of epithelial cells lining the lung, pancreas, liver, intestines, sweat duct, and the epididymis. The primary problem in CF is that mutations in CFTR affect its ability to be made, processed, and trafficked to the plasma membrane and/or its function as a Cl(-) channel and conductance regulator. Many proteins and processes normally interact with normal CFTR throughout its life cycle and mutant CFTR during the disease process. Understanding the function of these proteins and processes is expected to provide a clearer understanding of how normal CFTR is involved in salt movement and how mutant CFTR is handled by the cell and leads to the pathophysiology of CF. Recently, efforts to find therapies that correct defective CFTR have been intensifying. To facilitate our understanding of normal and mutant CFTR and the identification of new drug targets for developing novel therapies, a panel of experts was convened by the National Heart, Lung, and Blood Institute to explore the critical questions, challenges, and current opportunities to highlight new areas of research that would facilitate a integrated understanding of the processes and proteins that impact CFTR. The meeting highlighted the multiple pathways and interacting proteins involved in CFTR folding and biosynthesis, processing, and trafficking. A number of critical areas for future study were identified. Although these therapies are promising, a big question remains as to whether simply correcting defective CFTR will lead to significant improvement in patient health or whether the symptoms manifested in CF will require therapies in addition to those that target defective CFTR specifically.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Retículo Endoplásmico , Transporte Iónico , Sustancias Macromoleculares , Mutación , Membrana Celular/genética , Membrana Celular/fisiología , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Predicción , Humanos , Transporte Iónico/genética , Transporte Iónico/fisiología , Mutación/genética , Mutación/fisiología , Evaluación de Necesidades , Fragmentos de Péptidos/genética , Pliegue de Proteína , Mapeo de Interacción de Proteínas , Investigación/tendenciasRESUMEN
Over the last 20 years, the prevalence of asthma has nearly doubled and now affects 8-10% of the population in the United States. Asthma also remains a major illness in terms of morbidity and suffering, and is the leading cause of hospitalizations in children under 15 years of age. Because asthma poses a lifelong burden to patients and society, efforts to increase the understanding of its pathogenesis are a key factor leading to its control and cure. Consequently, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of extramural experts, entitled "Future Research Directions in Asthma," on April 9-10, 2003, to identify research areas of greatest promise and opportunity in the field of asthma. The priority areas identified for research in asthma include: (1) innate immunity, adaptive immunity, and tolerance; (2) mechanisms and consequences of persistent asthma and asthma exacerbations; (3) airway remodeling: clinical consequences and reversibility (clinical relevance and resolution); (4) genetics/gene-environment interactions, pharmacogenetics; (5) intervention/prevention/therapeutics; and (6) vascular basis of asthma.