RESUMEN
Dysregulation of mast cell function contributes to allergic and autoimmune disease that affects more than 70 million persons in the United States alone. Identifying novel mast cell targets that mediate disease or disease progression is required for the development of innovative therapeutics for the treatment of allergy/asthma and autoimmune disease. RNA interference technologies offer hope both as basic research tools for target identification and as potential, novel, specific therapeutics. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a family of evolutionarily conserved proteins that have been postulated to mediate the transport and fusion of inflammatory mediator-laden vesicles to the membrane in mast cells leading to their subsequent exocytosis. The functional role(s) of specific SNARE family member complexes in mast cell degranulation has not been fully elucidated. Here, we characterize the functional importance of SNARE complexes in FcεRI receptor-mediated degranulation of RBL-2H3 cells utilizing RNA interference. We demonstrate that ternary SNARE complexes of synaptosomal-associated protein-23, Syntaxin 4 and vesicle-associated membrane protein-7 (VAMP-7) or VAMP-8 are directly involved in mast cell degranulation. Additionally, we evaluate the siRNAs directed against these molecules as potential therapeutic agents for disease intervention. These studies have identified specific SNARE proteins and complexes that serve as novel targets for the development of siRNA therapies to treat allergic and autoimmune disease.
Asunto(s)
Degranulación de la Célula/inmunología , Regulación hacia Abajo/inmunología , Mastocitos/inmunología , ARN Interferente Pequeño/administración & dosificación , Proteínas SNARE/inmunología , Línea Celular , Humanos , Immunoblotting , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/inmunología , Proteínas Qb-SNARE/genética , Proteínas Qb-SNARE/inmunología , Proteínas Qc-SNARE/genética , Proteínas Qc-SNARE/inmunología , Proteínas R-SNARE/genética , Proteínas R-SNARE/inmunología , ARN/química , ARN/genética , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas SNARE/genéticaAsunto(s)
Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Animales , ADN/genética , ADN/ultraestructura , Humanos , Modelos Genéticos , Modelos Moleculares , Conformación de Ácido Nucleico , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-ets , Factores de Transcripción/químicaRESUMEN
Three methods of treating chalazia were compared in a controlled trial. Group A (conservative therapy of warm soaks and lid hygiene) consisted of six patients with seven chalazia. Group B (intralesional adrenocorticosteroid injection) had five patients with five chalazia. Group C (conservative therapy with intralesional steroid injection) included nine patients with ten chalazia. Success rates after six weeks of follow-up were: Group A: 3 of 7 (43%), Group B: 4 of 5 (80%), and Group C: 9 of 10 (90%). Intralesional steroid injection with or without concurrent conservative therapy was more effective than conservative management alone.
