Formation of the Elastin Line Element in the Developing Lung

发育中肺中弹性蛋白线元件的形成

• 批准号: 9190241
• 负责人: Cristian David Valenzuela
• 金额: $ 5.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190241
• 关键词: Address; Adult; Affect; Alveolar; Alveolar Duct; Alveolus; Anatomy; Architecture; Area; Bronchopulmonary Dysplasia; Chest; Chronic Obstructive Airway Disease; Collaborations; Congenital diaphragmatic hernia; Connective Tissue; Deposition; Development; Developmental Process; Disease; Elastin; Elastin Fiber; Electrons; Electrophoresis; Elements; Environmental air flow; Goals; Hospitals; Imaging Techniques; Indium; Knowledge; Lighting; Lung; Lung diseases; Maps; Mechanics; Medicine; Membrane; Mentorship; Methods; Microscopy; Neonatal; Parachuting; Peptides; Peripheral; Physiology; Positioning Attribute; Process; Pulmonary Fibrosis; Pulmonary Gas Exchange; Rattus; Research; Research Personnel; Scanning; Spatial Distribution; Staining method; Stains; Stretching; Structure; Structure of parenchyma of lung; Surface; System; Testing; Thick; Time; Tissues; Transplant Surgeon; Tropoelastin; Visceral; Woman; Work; abstracting; collaborative environment; connective tissue development; crosslink; lung development; macromolecule; malformation; medical schools; monomer; postnatal; postnatal human; reconstruction

Project Summary/Abstract The connective tissue system of the lung is critical for normal physiology of ventilation, and is perturbed in a wide range of disease: degradation in chronic obstructive pulmonary disease, thickening in pulmonary fibrosis, and malformation in bronchopulmonary dysplasia. The major conducting airways and the alveoli develop from axial and peripheral connective tissues, respectively. The alveolar duct is thought to be the anatomic unit at which these two major connective tissue systems integrate, structured by cable line elements (CLE) containing elastin, that maintain alveolar surface area over a range of conditions. Despite its importance, how the CLE initially forms during development remains unclear. Our lab is in a unique position to study CLE formation in the early postnatal rat lung, whose development closely resembles human postnatal lung development. Our main methods include electrophoresis staining of rat lung thick-sections containing intact alveolar ducts, tissue stretching using a customized platform, and structured- illumination epifluorescence microscopy for 3D reconstruction. In the early rat lung, we have recently discovered marked broad random deposition of precursor tropoelastin “spheres” into the primary septa by postnatal day 4, and conversion into adult-like CLEs by day 21. Since the absence of stretch during lung development is known to interfere with elastin architecture formation, this led to our hypothesis that the CLE forms in the developing lung as a result of a directional stretch field applied to a random distribution of tropoelastin spheres. We have induced the formation of CLE-like structures using mechanical stretch on lung tissue ex vivo, recapitulating this step of normal development. The overall goals of this proposal are to (1) map the developmental process by which the CLE forms from tropoelastin in the developing lung, and (2) experimentally manipulate stretch fields on lung tissue to clarify how directionality of a stretch field influences CLE formation. A better understanding of lung microstructure development is expected to have a positive impact for conditions in which the connective tissue architecture is affected, including chronic obstructive pulmonary disease, pulmonary fibrosis, and bronchopulmonary dysplasia. In this two-year project, Dr. Valenzuela will work under the close mentorship of his sponsor, Dr. Steven Mentzer (thoracic/transplant surgeon), and in collaboration with Dr. Akira Tsuda (expert in lung microstructure and development), within the highly collaborative environment of Brigham and Women’s Hospital at Harvard Medical School. This project will help develop Dr. Valenzuela into an independent researcher and leader in academic medicine.

项目摘要/摘要 肺的连接组织系统对于通气的正常生理至关重要，并且是 在多种疾病中受到干扰：慢性阻塞性肺疾病的降解， 肺纤维化增厚和支气管肺发育不良的畸形。专业 进行气道和肺泡从轴向和周围连接的时机发展， 分别。肺泡管被认为是这两个主要的解剖单元 结缔组织系统集成，由包含弹性蛋白的电缆线元素（CLE）结构， 在一系列条件下，它可以维持牙槽表面积。尽管很重要，但如何 最初在开发过程中的形式尚不清楚。我们的实验室处于研究CLE的独特位置 早期出生后大鼠肺的形成，其发育与人类后产后相似 肺发育。我们的主要方法包括大鼠肺厚截面的电泳染色 包含完整的肺泡管，使用定制平台拉伸组织，结构化 - 用于3D重建的照明表荧光显微镜。在早期的老鼠肺中，我们有 最近发现的明显的前体tropoelastin“球”的广泛随机沉积到了 原发性隔出第4天，在第21天之前转换为类似成人的cles。 众所周知，肺发育过程中缺乏拉伸会干扰弹性蛋白结构 形成，这导致了我们的假设，即由于A 定向伸展场应用于tropoelastin球的随机分布。我们已经诱发了 使用机械伸展在肺组织后的机械拉伸形成，概括 正常发展的这一步骤。该提案的总体目标是（1）映射 发育过程从发育中的肺中的Tropoelastin形成CLE，（2） 实验操纵肺组织上的拉伸场，以阐明拉伸场的方向性 影响CLE形成。预计将更好地了解肺微结构的发展 为了对结缔组织结构的条件产生积极影响， 包括慢性阻塞性肺部疾病，肺纤维化和支气管肺 发育不良。在这个为期两年的项目中，瓦伦苏埃拉博士将在他的紧密心态下工作 赞助商史蒂文·曼特策（Steven Mentzer）博士（胸外科医生），并与Akira博士合作 Tsuda（肺微结构和开发专家），在高度协作的环境中 哈佛医学院的杨百翰和妇女医院。该项目将有助于发展博士。 瓦伦苏埃拉（Valenzuela）成为一位独立的研究员和学术医学领导者。

项目成果

Water-Dependent Blending of Pectin Films: The Mechanics of Conjoined Biopolymers.

果胶膜的水依赖性混合：联合生物聚合物的力学。

• DOI: 10.3390/molecules25092108
• 发表时间: 2020
• 期刊: Molecules (Basel, Switzerland)
• 作者: Zheng,Yifan;Pierce,Aidan;Wagner,WilliL;Scheller,HenrikV;Mohnen,Debra;Ackermann,Maximilian;Mentzer,StevenJ
• 通讯作者: Mentzer,StevenJ

Optical and Mechanical Properties of Self-Repairing Pectin Biopolymers.

• DOI: 10.3390/polym14071345
• 发表时间: 2022-03-26
• 期刊: POLYMERS
• 影响因子: 5
• 作者: Pierce, Aidan F.;Liu, Betty S.;Liao, Matthew;Wagner, Willi L.;Khalil, Hassan A.;Chen, Zi;Ackermann, Maximilian;Mentzer, Steven J.
• 通讯作者: Mentzer, Steven J.