Inhibition of Mucin Secretion in Murine Model of Asthma

哮喘小鼠模型中粘蛋白分泌的抑制

• 批准号: 6646157
• 负责人: Indu Parikh
• 金额: $ 10万
• 依托单位: BIOMARCK PHARMACEUTICALS, LTD
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646157
• 关键词: actin binding protein; asthma; disease /disorder model; enzyme linked immunosorbent assay; high performance liquid chromatography; histology; laboratory mouse; lung lavage; methacholine; mucins; ovalbumin; peptide analog; pilocarpine; protein sequence; protein structure function; respiratory pharmacology; respiratory system; technology /technique development

DESCRIPTION (provided by applicant): Hypersecretion of mucus into the respiratory airways is a major factor in several lung diseases, including chronic bronchitis, asthma, cystic fibrosis, and bronchiectasis. Despite the obvious medical importance, mechanisms that regulate production and secretion of airway mucus have not been elucidated fully, and, relatedly, there presently are no effective therapies to control excess mucus secretion in disease, and very few potential therapeutic targets. In previous NIH-funded research from the laboratories of the scientific consultants, a key molecule in the secretory pathway in human airway goblet cells was described. This molecule, MARCKS protein (Myristoylated Alanine-Rich C Kinase Substrate) plays a major role in regulating secretion of mucus in well-differentiated human airway epithelial cells in vitro. In the course of these studies, we developed a peptide to inhibit the function of MARCKS. The peptide corresponds to the N-terminal region of the MARCKS molecule. The peptide, named the MANS peptide, inhibits secretion of mucus by normal human bronchial epithelial (NHBE) cells in tissue culture in response to exogenous stimulation. A control peptide, consisting of the same N-terminal amino acids, but arranged in random order, has no effect. In the present application, we wish to determine if this peptide, instilled intratracheally into asthmatic mice that secrete excessive amounts of mucus can, similar to its effects in vitro, inhibit mucus secretion in vivo. If successful, these studies will be expanded in Phase II to include additional species, efficacy and toxicity studies, and research to optimize peptide solubility and stability; steps necessary for commercial development. The long-term goal is to develop a novel treatment that reduces mucus hypersecretion in the respiratory tract by directly blocking a step in the intracellular secretory pathway.

描述（由申请人提供）：呼吸道粘液分泌过多是多种肺部疾病的主要因素，包括慢性支气管炎、哮喘、囊性纤维化和支气管扩张。尽管具有明显的医学重要性，但调节气道粘液产生和分泌的机制尚未完全阐明，并且相关地，目前没有有效的治疗方法来控制疾病中的过度粘液分泌，并且几乎没有潜在的治疗靶点。 在之前NIH资助的科学顾问实验室的研究中，描述了人类气道杯状细胞分泌途径中的关键分子。这种分子MARCKS蛋白（肉豆蔻酰化富含丙氨酸的C激酶底物）在体外调节分化良好的人气道上皮细胞中粘液分泌方面起主要作用。在这些研究的过程中，我们开发了一种肽来抑制MARCKS的功能。该肽对应于MARCKS分子的N-末端区域。该肽被命名为MANS肽，抑制组织培养中正常人支气管上皮（NHBE）细胞对外源性刺激的粘液分泌。由相同的N-末端氨基酸组成，但以随机顺序排列的对照肽没有影响。 在本申请中，我们希望确定将这种肽经气管内滴注到分泌过量粘液的哮喘小鼠中是否可以与其体外作用类似地抑制体内粘液分泌。如果成功，这些研究将在II期扩大，以包括其他物种、功效和毒性研究，以及优化肽溶解度和稳定性的研究;商业开发所需的步骤。长期目标是开发一种新的治疗方法，通过直接阻断细胞内分泌途径中的一个步骤来减少呼吸道中的粘液分泌过多。