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siRNA-mediated identification and regulation of the ternary SNARE complex mediating mast cell degranulation.

机译：siRNA介导的三元SNARE复合物介导肥大细胞脱粒的鉴定和调控。

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摘要

The identification of mast cell protein targets that mediate disease or disease progression is critical for the development of novel therapeutics for the treatment of allergy/asthma and autoimmune disease. Mast cells are granulocytes that emanate from myeloid progenitors in the bone marrow and play a critical role in innate immunity as vital sentinel cells that combat invading microorganisms through the release of a plethora of inflammatory mediators. Dysregulation of mast cell function leads to allergic disease and autoimmune disease that affect millions of people in the United States alone. Within cells, the transport and fusion of inflammatory mediator-laden vesicles to the membrane in granulocytes and their subsequent exocytosis is mediated by a family of evolutionarily-conserved proteins known as the SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors). The expression and functional roles of the SNARE family protein members in mast cell degranulation has not been elucidated. Here, we evaluate mast cell SNARE expression profiles at the mRNA and protein levels and determine the candidate SNARE proteins mediating mast cell degranulation in RBL-2H3 cells. We use immunoprecipitation to characterize the pertinent ternary SNARE complexes that interact following cell activation. We demonstrate that these complexes are critical for mast cell degranulation by utilizing RNA interference (siRNA) to knockdown mRNA and protein levels of the individual constituent SNARE proteins during FcepsilonRI receptor-activated rat RBL-2H3 mast cell activation. We use SNARE gene overexpression studies to confirm the phenotypes discovered using siRNA. We have identified specific SNARE proteins and complexes mediating mast cell degranulation in RBL-2H3 cells. Further, we have established sets of specific siRNA oligomers to begin the development of novel nucleic acid therapeutics to treat allergic and autoimmune disease.
机译：鉴定介导疾病或疾病进展的肥大细胞蛋白靶标对于开发用于治疗变应性/哮喘和自身免疫性疾病的新型疗法至关重要。肥大细胞是从骨髓中的髓祖细胞发出的粒细胞，在先天免疫中起着至关重要的作用，它是重要的前哨细胞，通过释放过多的炎症介质来对抗入侵的微生物。肥大细胞功能失调会导致仅在美国影响数百万人的变态反应性疾病和自身免疫性疾病。在细胞内，载有炎性介质的囊泡在粒细胞中的转运和融合以及随后的胞吐作用是由一类进化上保守的蛋白质（称为SNARE）（可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体）介导的。尚不清楚SNARE家族蛋白成员在肥大细胞脱粒中的表达和功能作用。在这里，我们评估mRNA和蛋白质水平的肥大细胞SNARE表达谱，并确定介导RBL-2H3细胞肥大细胞脱粒的候选SNARE蛋白。我们使用免疫沉淀来表征细胞激活后相互作用的相关三元网罗配合物。我们证明这些复合物通过利用RNA干扰（siRNA）在FcepsilonRI受体激活的大鼠RBL-2H3肥大细胞激活过程中利用RNA干扰（siRNA）敲低单个组成的SNARE蛋白的mRNA和蛋白水平，对于肥大细胞脱粒至关重要。我们使用SNARE基因过表达研究来确认使用siRNA所发现的表型。我们已经确定了特定的SNARE蛋白和复合物介导RBL-2H3细胞中肥大细胞脱粒。此外，我们已经建立了一组特定的siRNA寡聚物，以开始开发新的核酸疗法来治疗变应性和自身免疫性疾病。

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  • 作者

    Woska, Joseph R., Jr.;

  • 作者单位

    St. John's University (New York), School of Pharmacy.;

  • 授予单位 St. John's University (New York), School of Pharmacy.;
  • 学科 Health Sciences Pharmacology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 109 p.
  • 总页数 109
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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