Inhibition of Mucin Secretion in Murine Model of Asthma

描述(申请人提供)：粘液过度分泌到呼吸道是几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。尽管有明显的医学重要性，但调节呼吸道粘液的产生和分泌的机制尚未完全阐明，与之相关的是，目前还没有有效的治疗方法来控制疾病中过度的粘液分泌，而且几乎没有潜在的治疗靶点。 在之前由NIH资助的科学顾问实验室的研究中，描述了人类气道杯细胞分泌途径中的一个关键分子。这种分子，Marcks蛋白(肉豆蔻酰化的富含丙氨酸的C激酶底物)在体外调节分化良好的人呼吸道上皮细胞粘液的分泌方面发挥着重要作用。在这些研究过程中，我们开发了一种抑制Marcks功能的多肽。该肽对应于Marcks分子的N-末端区域。这种多肽被称为MANS肽，在组织培养中抑制正常人类支气管上皮(NHBE)细胞对外界刺激的粘液分泌。由相同的N-末端氨基酸组成但随机排列的控制肽不起作用。 在目前的应用中，我们希望确定这种多肽，气管内滴注到分泌过量粘液的哮喘小鼠体内，是否可以抑制体内粘液的分泌，类似于它在体外的作用。如果成功，这些研究将在第二阶段扩大，包括更多的物种、有效性和毒性研究，以及优化多肽溶解度和稳定性的研究；这些步骤是商业开发所必需的。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的一个步骤来减少呼吸道粘液的过度分泌。

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.