Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis

特发性肺纤维化的建模、发病机制和治疗

• 批准号: 10192798
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 126.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192798
• 关键词: Address; Affect; Animal Model; Animals; Biomedical Engineering; Cell Lineage; Cell Therapy; Cell physiology; Cells; Clinical; Collaborations; Communication; Derivation procedure; Development; Disease; Distal; Drug Delivery Systems; Drug Targeting; Epithelial; Epithelial Cells; Event; Excision; Family suidae; Fibrosis; Fostering; Funding; Gene Delivery; Gene Transfer Techniques; Generations; Genes; Genetic Predisposition to Disease; Goals; Heart; Human; Immunologics; Inbreeding; Injury; Institution; Interstitial Lung Diseases; Intervention; Joints; Link; Lung; Lung Transplantation; Lung diseases; Medical; Methods; Miniature Swine; Modality; Modeling; Mus; Mutation; Operative Surgical Procedures; Organ Donor; Outcome; Output; Parents; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmacology; Physiology; Pluripotent Stem Cells; Preclinical Testing; Process; Prognosis; Publications; Pulmonary Fibrosis; Rattus; Recording of previous events; Research; Research Personnel; Risk; Role; Scientific Advances and Accomplishments; Source; Structure of parenchyma of lung; System; Technology; Therapeutic; Therapeutic Intervention; Thoracic Surgical Procedures; Tissues; Transplantation; Validation; alveolar epithelium; curative treatments; design; disease mechanisms study; drug discovery; end stage disease; human pluripotent stem cell; idiopathic pulmonary fibrosis; image guided; imaging modality; improved; innovation; insight; interdisciplinary approach; lung development; lung injury; lung preservation; lung regeneration; mouse model; novel therapeutic intervention; novel therapeutics; porcine model; pre-clinical; preservation; prevent; regenerative approach; scaffold; stem cell biology; stem cells; surfactant; therapeutic evaluation

Idiopathic pulmonary fibrosis (IPF) is an intractable interstitial lung disease characterized by fibroblastic foci, remodeling and obliteration of alveoli, and a median survival of 3 to 4 years. The only definitive treatment is lung transplantation, an intervention hampered by low availability of donor organs, and severe surgical and immunological complications. Innovative approaches are therefore urgently needed. We identified three major challenges towards improving the prognosis of IPF, and propose to address these challenges in the three research hubs of our consortium: (1) Cell sources should be established to study pathogenesis of IPF and to eventually prevent or reverse fibrosis. In Hub 1, we propose directed differentiation of human pluripotent stem cells (hPSCs) into lung tissue to investigate pathogenesis and establish platforms for drug discovery. (2) Cell removal/delivery methods are needed to either replace irreversibly damaged lung tissue, or the cells that carry pathogenesis of IPF. In Hub 2, we will develop the necessary bioengineering modalities that will take advantage of directed differentiation of hPSCs into lung tissue. (3) The field requires a large animal model for the validation of pathogenetic mechanisms and preclinical validation of novel therapeutic modalities for IPF developed by the first two research hubs. We therefore propose to establish a miniature swine model for IPF to validate pathogenetic mechanisms discovered in Hub1, and cellular replacement approaches developed in Hub 2. The overarching goal of this proposal is to gain desperately needed insight into the pathogenesis of IPF (Hub 1) and to use these insights to inform the development of novel therapeutic approaches for IPF (Hub 2). As IPF is currently an untreatable disease, it is not possible to predict which approaches will be beneficial, and the therapy may be dictated by disease stage. Pharmacological approaches may target the fibrotic process itself, or pathways emanating from epithelial cells that initiate this process and would likely be useful in early stage disease or in patients that are genetically predisposed. Regenerative approaches could consist of cellular therapies, in particular targeting ATII cells, most likely early in disease or in patients predisposed to IPF, but may extend to transplantation of recellularized lung scaffolds in end-stage disease. Both types of regenerative approaches will require bioengineering technologies that will be developed Hub 2 and informed by a deeper understanding of IPF pathogenesis achieved in Hub 1. Ultimately, verification of disease mechanism and preclinical testing of therapeutic approaches requires a large animal model, which is the focus of Hub 3.

特发性肺纤维化（IPF）是一种以成纤维细胞灶为特征的难治性间质性肺疾病， 肺泡重塑和闭塞，中位生存期为3至4年。唯一有效的治疗方法是 肺移植，一种因供体器官可用性低而受阻的干预措施，以及严重的外科手术和 免疫并发症因此，迫切需要采取创新办法。我们确定了三个主要的 改善IPF预后的挑战，并建议在三个方面应对这些挑战 我们的联合体的研究中心：（1）应建立细胞来源，以研究IPF的发病机制， 最终预防或逆转纤维化。在Hub 1中，我们提出了人类多能干细胞的定向分化， 细胞（hPSC）进入肺组织，以研究发病机制并建立药物发现平台。(2)细胞 需要移除/递送方法来替换不可逆地受损的肺组织或携带肺细胞的细胞。 IPF的发病机制。在Hub 2中，我们将开发必要的生物工程模式， 这是hPSC定向分化为肺组织的优点。(3)该领域需要大型动物模型， IPF发病机制的验证和新型治疗方式的临床前验证 由前两个研究中心开发。因此，我们建议建立IPF的小型猪模型， 验证在Hub 1中发现的发病机制，以及在 2号枢纽该提案的总体目标是获得急需的IPF发病机制的见解 (Hub 1）并利用这些见解为IPF新型治疗方法的开发提供信息（Hub 2）。 由于IPF目前是一种无法治疗的疾病，因此无法预测哪种方法将有益， 治疗可以由疾病阶段决定。药理学方法可以针对纤维化过程 本身，或从上皮细胞发出的途径，启动这一过程，并可能是有用的，在早期 阶段性疾病或在有遗传倾向的患者中。再生方法可能包括 细胞疗法，特别是靶向ATII细胞，最有可能在疾病早期或易患 IPF，但可能扩展到终末期疾病中再细胞化肺支架的移植。两种类型的 再生方法将需要生物工程技术，这些技术将由Hub 2开发， 通过在Hub 1中实现对IPF发病机制的更深入理解。最终，疾病的验证 治疗方法的机制和临床前测试需要大型动物模型，这是重点 Hub 3的