Reconstructing native soluble cues in vascularized whole lung scaffolds

重建血管化全肺支架中的天然可溶性线索

• 批准号: 10878030
• 负责人: Yifan Yuan
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10878030
• 关键词: Acute Respiratory Distress Syndrome; Adult; Alveolus; BMP5 gene; Biological Models; Biomimetics; Bioreactors; Blood Vessels; COVID-19; Capillary Leak Syndrome; Cell Maturation; Cells; Characteristics; Cues; Data; Data Set; Development; Disease; Disease model; Distal; Drug Screening; Endothelial Cells; Endothelium; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Functional disorder; Genomics; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Inhalation; Injury; Interferon Type II; Lipopolysaccharides; Lung; Lung diseases; Microfluidics; Modeling; Organ; Organoids; Paracrine Communication; Phase; Phenotype; Physiological; Physiology; Property; Publishing; Sepsis; Signal Induction; Signal Transduction; Structure; System; TNF gene; Thrombus; Trees; Vascular Endothelium; Vascular Permeabilities; Vascularization; Work; computerized tools; cytokine; drug candidate; drug mechanism; drug testing; hemodynamics; improved; novel; novel coronavirus; paracrine; primary pulmonary hypertension; pulmonary vascular disorder; scaffold; shear stress; single-cell RNA sequencing; solute; tissue culture; tool; vascular factor

Project Abstract Diseases of the lung vasculature, including capillary leak syndrome/acute respiratory distress syndrome (ARDS), inhalation injury, primary pulmonary hypertension, and the novel coronavirus disease-19 (COVID-19), are difficult to study due to the lack of functional ex vivo models. Conventional culture systems are typically limited in their ability to represent human pathophysiology for the study of disease and drug mechanisms. The overall objective of this proposal is to develop an experimental platform that mimics the pulmonary microvasculature, and that can simulate native cellular phenotypes and functions in vitro, during normal homeostasis and during disease states such as severe inflammation, and sepsis. The lung microvascular niche characteristics, such as paracrine factors, hemodynamics, and extracellular matrix composition are all of pivotal importance for regulating endothelial maturation and maintaining vascular homeostasis. Whole organ decellularization opens a door to provide a construct that recapitulates the substrate structure and components of an entire vascular tree. Additionally, leveraging single-cell RNA-seq (scRNAseq), we developed computational tools to identify the paracrine signals in human distal lungs. In this study, I will leverage these tools to identify novel, important locally acting soluble factors in a functional lung microvascular niche to improve pulmonary microvascular maturation in acellular lung scaffolds. During the K99 phase of this proposal, I will first leverage our published scRNAseq computational tools to evaluate the scRNAseq dataset on native adult human lungs. I will determine a group of important and novel soluble factors that could improve endothelial maturation. Then, I will rationally iterate on our endothelial repopulated lung platform with the addition of relevant soluble factors derived from the native microvascular milieu. During the R00 phase, I will use the vascular platform established in prior aims and start to develop a disease modeling system to study the impact of inflammation for drug testing. This work will lead to the creation of a novel platform which, unlike previous microvascular platforms, specifically resembles many physiological aspects of the native lung environment. Such a platform could be used for pulmonary vascular disease modeling and drug testing.

项目摘要 肺脉管系统的疾病，包括毛细血管泄漏综合征/急性呼吸窘迫综合征 （ARDS），吸入损伤，原发性肺动脉高压和新型冠状病毒病19（Covid-19）， 由于缺乏功能性离体模型，很难研究。常规文化系统通常是 他们代表人类病理生理学的能力有限，以研究疾病和药物机制。这 该建议的总体目的是开发一个模拟肺的实验平台 在正常情况下，微举行的微脉管系统可以模拟天然细胞表型和功能 体内平衡和疾病状态，例如严重的炎症和败血症。肺微血管 利基特征，例如旁分泌因子，血液动力学和细胞外基质组成是所有的 对于调节内皮成熟和维持血管稳态的关键重要性。整个器官 脱落打开了一扇门，以提供概括底物结构和组件的构造 整个血管树。此外，利用单细胞RNA-Seq（Scrnaseq），我们开发了 识别人远端肺中旁分泌信号的计算工具。在这项研究中，我将利用这些 识别功能性肺微血管小众中新颖，重要的本地作用可溶性因子的工具 改善细胞肺支架中的肺微血管成熟。在此提案的K99阶段， 我将首先利用我们已发布的Screnaseq计算工具来评估本机上的scrnaseq数据集 成人人类肺。我将确定一组重要和新颖的可溶性因素，这些因素可以改善 内皮成熟。然后，我将在我们的内皮重新填充的肺平台上合理迭代 从天然微血管环境中得出的相关可溶性因子的添加。在R00阶段，我将 使用以前目标建立的血管平台，并开始开发疾病建模系统来研究 炎症对药物测试的影响。这项工作将导致创建一个新颖的平台，与 以前的微血管平台，特别类似于天然肺的许多生理方面 环境。这样的平台可用于肺血管疾病建模和药物测试。