权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Lung Fibrosis in an Hermansky-Pudlak Syndrome Mouse Model

赫曼斯基-普德拉克综合征小鼠模型中的肺纤维化

基本信息

批准号：
7367381
负责人：
Tim Arden Lyerla
金额：
$ 22.35万
依托单位：
CLARK UNIVERSITY (WORCESTER, MA)
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367381
关键词：
Adaptor Signaling Protein Affect Age Age-Years Aging Alveolar Alveolar Macrophages Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Appearance Biological Biological Assay Bleomycin Blood Platelets Cells Cessation of life Collagen Continuous Infusion Cultured Cells Deposition Development Disease Dose Ear Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Exhibits Fibrosis Genes Goals Hereditary Disease Hermanski-Pudlak Syndrome Human Hydroxyproline In Situ Nick-End Labeling In Vitro Individual Inflammatory Interstitial Pneumonia Investigation Irrigation Laboratories Lesion Life Lipopolysaccharides Lung Lung Inflammation Lysosomes Melanosomes Methods Modeling Mouse Strains Mus Mutant Strains Mice Nature Newborn Infant Nitric Oxide Organelles Pathway interactions Pharmaceutical Preparations Piebaldism Primary Cell Cultures Process Production Property Publishing Pulmonary Fibrosis Pump Range Reaction Reporting Role Sampling Syndrome System TFF1 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Trichrome stain Vesicle Work Writing alveolar type II cell caspase-3 cell type cytokine day indium-bleomycin insight juvenile animal mouse model mutant surfactant trafficking

项目摘要

DESCRIPTION (provided by applicant): Hermansky Pudlak Syndrome (HPS) is a rare, but serious genetic disorder of partial albinism with pleiotropic effects on platelet dense bodies, melanosomes, and lysosome-related organelles. While effects on platelets and melanosomes are generally moderate or clinically manageable, progressive pulmonary fibrosis (HPS interstitial pneumonia, or HPSIP) can be a consequence of this disorder, which is debilitating and results in premature death. The long-term objective of this project is to establish the authenticity of an animal model for HPS lung fibrosis that will be useful for testing possible therapeutic interventions. A double homozygous HPS mouse model (C57BL/6-HPS1ep Ap3b1pe-J) that mimics human HPS lung abnormalities, especially enlarged surfactant bearing lysosome-like organelles of the alveolar type II cells, will be used in these studies. Preliminary studies with this mutant in our laboratory have shown that some, but not all older animals raised in an open colony develop fibrotic lesions in the lung, and that classical markers of fibrosis including Masson's trichrome staining and hydroxyproline levels show deposition of collagen in young as well as older animals of this strain. We have also shown increased levels of TGF-(1 in bronchial alveolar lavage (BAL) samples from these mice and highly activated alveolar macrophages in cultures of these cells from BAL samples. Specific aims in these studies include the use of high-dose continuous infusion of bleomycin to produce progressive lung fibrosis in this strain, assessment of the biological properties of the morphologically activated alveolar macrophages, and a detailed analysis of apoptosis in the lungs of this HPSIP mouse model using ELISA and immunohistochemisty methods. Results from the double mutant animals will be compared with age matched C57BL/6J+/+ and C57BL/6-Lystbg/Lystbg-J beige mutants. The latter strain shares a dysmorphic alveolar type II cell abnormality with the HPS double mutant, but not alveolar macrophage abnormalities, the development of sporadic cases of pulmonary fibrosis, or increasing levels of collagen with aging. The results from these investigations will determine the authenticity of the C57BL/6-HPS1ep Ap3b1pe-J mouse strain as an animal model for HPS lung fibrosis. Project Narrative: Hermansky-Pudlak Syndrome (HPS) is a rare, heterogeneous genetic disorder affecting lysosome-related organelles, including melanosomes, platelet dense bodies, and alveolar type II epithelial cells. The most challenging and life-threatening aspect of this heritable disease is its effect on the lungs, which results in pulmonary fibrosis in most cases of HPS1 individuals. An HPS mouse that is homozygous recessive for two HPS genes affecting separate pathways of vesicle trafficking, C57BL/6- HPS1ep/ HPS1ep; HPS2Apb3pe/ HPS2Apb3pe-J, has been used in this laboratory as a model for the human disorder, and some animals develop lung fibrosis at late ages when raised in an open colony. The proposed studies investigate whether this model can be made more useful by inducing pulmonary fibrosis in young animals that better mimics the progressive, ultimately fatal disorder in affected humans. Studies of the highly activated alveolar macrophages seen in the double mutant HPS mouse model are also planned that will provide a better understanding of their possible role in early inflammation of the lung, as well as studies of apoptosis in the lungs of this HPS model. These investigations will yield insights on a mouse model for HPS that should help in assessing possible therapeutic strategies for overcoming progressive pulmonary fibrosis.

描述（由申请人提供）：Hermansky Pudlak综合征（HPS）是一种罕见但严重的部分白化病遗传性疾病，对血小板致密体、黑素体和溶酶体相关细胞器具有多效性作用。虽然对血小板和黑素体的影响通常是中度或临床可管理的，但进行性肺纤维化（HPS间质性肺炎或HPSIP）可能是这种疾病的后果，这会使人衰弱并导致过早死亡。该项目的长期目标是建立HPS肺纤维化动物模型的真实性，这将有助于测试可能的治疗干预措施。在这些研究中将使用模拟人HPS肺异常的双纯合HPS小鼠模型（C57 BL/6-HPS 1 ep Ap 3b 1 pe-J），特别是肺泡II型细胞的溶酶体样细胞器的增大的表面活性剂。在我们实验室中对这种突变体的初步研究表明，在开放群体中饲养的一些但不是所有老年动物在肺中发生纤维化病变，并且纤维化的经典标志物包括Masson三色染色和羟脯氨酸水平显示该品系的年轻和老年动物中胶原蛋白沉积。我们还发现这些小鼠的支气管肺泡灌洗（BAL）样品中TGF-β 1水平升高，BAL样品中这些细胞培养物中的肺泡巨噬细胞高度活化。这些研究的具体目的包括使用高剂量连续输注博来霉素以在该品系中产生进行性肺纤维化，评估形态学活化的肺泡巨噬细胞的生物学特性，以及使用ELISA和荧光化学方法详细分析该HPSIP小鼠模型肺中的细胞凋亡。将双突变体动物的结果与年龄匹配的C57 BL/6 J +/+和C57 BL/6-Lystbg/Lystbg-J米色突变体进行比较。后一种菌株与HPS双突变体共享畸形肺泡II型细胞异常，但不包括肺泡巨噬细胞异常、肺纤维化的偶发病例的发展或胶原蛋白水平随年龄增加。这些研究的结果将确定C57 BL/6-HPS 1 ep Ap 3b 1 pe-J小鼠品系作为HPS肺纤维化动物模型的真实性。项目叙述：Hermansky-Pudlak综合征（HPS）是一种罕见的异质性遗传疾病，影响溶酶体相关的细胞器，包括黑素体，血小板致密体和肺泡II型上皮细胞。这种遗传性疾病最具挑战性和威胁生命的方面是其对肺部的影响，这导致大多数HPS 1个体病例中的肺纤维化。本实验室已将影响囊泡运输不同途径的两个HPS基因C57 BL/6-HPS 1 ep/HPS 1 ep; HPS 2Apb 3 pe/HPS 2Apb 3 pe-J的纯合隐性HPS小鼠用作人类疾病的模型，并且当在开放群体中饲养时，一些动物在晚期发生肺纤维化。拟议的研究调查了这种模型是否可以通过在年轻动物中诱导肺纤维化而变得更有用，从而更好地模拟受影响人类的进行性，最终致命的疾病。还计划对双突变HPS小鼠模型中观察到的高度活化的肺泡巨噬细胞进行研究，这将更好地了解它们在肺部早期炎症中的可能作用，以及对该HPS模型肺部细胞凋亡的研究。这些研究将产生对HPS小鼠模型的见解，这将有助于评估克服进行性肺纤维化的可能治疗策略。