Utilizing induced pluripotent stem cells to study the role of alveolar type 2 cell dysfunction in pulmonary fibrosis

利用诱导多能干细胞研究肺泡2型细胞功能障碍在肺纤维化中的作用

基本信息

批准号：
10591174
负责人：
Konstantinos Alysandratos
金额：
$ 16.22万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591174
关键词：
Adult Alveolar Biogenesis Biological Models Boston Cell Differentiation process Cell Line Cells Cessation of life Childhood Critical Care Data Data Set Defect Development Diagnosis Disease Disease model Epithelium Event FDA approved Fibroblasts Fibrosis Functional disorder Future Gases Genes Genetic study Genotype Goals Human Hypersensitivity Idiopathic Interstitial Pneumonia Immune Impairment In Vitro Inflammatory International Interstitial Lung Diseases K-Series Research Career Programs Literature Lung Lung diseases Manuscripts Medicine Mentors Mesenchymal Mesenchyme Metabolic Methods Mitochondria Modeling Morbidity - disease rate Morphology Mutant Strains Mice Mutation Organoids Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Physicians Pirfenidone Pluripotent Stem Cells Population Preparation Proteomics Publishing Pulmonary Fibrosis Recombinants Regenerative Medicine Research Role Scientist Sleep Stress Structure of parenchyma of lung Syndrome Systems Biology Testing Time Training Training Programs Universities Variant alveolar epithelium career development disorder risk effective therapy fibrogenesis genome wide association study genomic locus human disease human model idiopathic pulmonary fibrosis in vitro Model in vivo in vivo evaluation induced pluripotent stem cell lung development meetings member mitochondrial dysfunction molecular phenotype mortality mouse model new therapeutic target nintedanib novel novel strategies novel therapeutics proteostasis pulmonary function decline self-renewal single-cell RNA sequencing stem cell biology stem cell model stem cells timeline transcriptomics

Adult Alveolar Biogenesis Biological Models Boston Cell Differentiation process Cell Line Cells Cessation of life Childhood Critical Care Data Data Set Defect Development Diagnosis Disease Disease model Epithelium Event FDA approved Fibroblasts Fibrosis Functional disorder Future Gases Genes Genetic study Genotype Goals Human Hypersensitivity Idiopathic Interstitial Pneumonia Immune Impairment In Vitro Inflammatory International Interstitial Lung Diseases K-Series Research Career Programs Literature Lung Lung diseases Manuscripts Medicine Mentors Mesenchymal Mesenchyme Metabolic Methods Mitochondria Modeling Morbidity - disease rate Morphology Mutant Strains Mice Mutation Organoids Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Physicians Pirfenidone Pluripotent Stem Cells Population Preparation Proteomics Publishing Pulmonary Fibrosis Recombinants Regenerative Medicine Research Role Scientist Sleep Stress Structure of parenchyma of lung Syndrome Systems Biology Testing Time Training Training Programs Universities Variant alveolar epithelium career development disorder risk effective therapy fibrogenesis genome wide association study genomic locus human disease human model idiopathic pulmonary fibrosis in vitro Model in vivo in vivo evaluation induced pluripotent stem cell lung development meetings member mitochondrial dysfunction molecular phenotype mortality mouse model new therapeutic target nintedanib novel novel strategies novel therapeutics proteostasis pulmonary function decline self-renewal single-cell RNA sequencing stem cell biology stem cell model stem cells timeline transcriptomics

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项目摘要

Project Summary This proposal details a 5-year career development training program focused on developing a patient-specific induced pluripotent stem cell (iPSC) model system to study the role of alveolar epithelial type 2 (AT2) cell dysfunction at the inception of pulmonary fibrosis (PF). A growing literature now implicates alveolar epithelial dysfunction as playing a role in the events that lead to downstream fibroblast activation culminating in relentless fibrosis in a variety of interstitial lung disease (ILD) syndromes, including adult idiopathic PF (IPF) and childhood ILD (chILD). However, without access to patient-specific human epithelial-mesenchymal model systems, there are limited options for testing hypotheses of how AT2 cell dysfunction leads to disease in humans. The outlined proposal builds on an in vitro human model system recently developed and published by the candidate to better understand the mechanisms by which AT2 cell dysfunction in the context of the most common disease- associated SFTPC variant (SFTPCI73T) leads to PF. The mechanisms identified by studying AT2 cell dysfunction using the in vitro iPSC-derived model will be further validated in vivo in SftpcI73T mutant mice. More specifically, the aims of this proposal are to: 1) study the role of AT2 cell dysfunction and the downstream consequences of epithelial dysfunction in eliciting a fibrotic cascade by utilizing a novel human patient-specific iPSC in vitro epithelial-mesenchymal recombinant model system, 2) test the hypothesis that AT2 cell-intrinsic perturbations characterized by proteostasis defects and metabolic reprograming result in impaired AT2-to-AT1 cell differentiation, inflammatory activation, and fibrogenic mesenchymal activation, and 3) identify druggable pathways for novel PF therapies by testing novel approaches to restore AT2 cell proteostasis and mitochondrial function. Both the model system to be developed and the pathogenic mechanisms to be revealed likely will be generalizable to a broad diversity of PF phenotypes, providing novel druggable targets for both familial and sporadic PF therapies. Dr. Alysandratos has 80% protected time from the Division of Pulmonary, Allergy, Sleep & Critical Care Medicine and the Boston University Department of Medicine. His mentor, Dr. Darrell Kotton at the Center for Regenerative Medicine (CReM), is an international expert in stem cell biology with a focus on applying stem cells to model and understand lung development and disease, making him ideally suited for this career development award focused on iPSC-model systems of PF. A team of extraordinary scientific advisory members, each bringing their specific expertise, has been carefully assembled to provide complementary guidance. A detailed training plan is presented that includes mentored research, didactic coursework, presentations at meetings, and a timeline for completion of the research aims, preparation of manuscripts, and future R01 application. At the completion of this proposal, the candidate will have developed the necessary expertise to successfully transition into an independent physician-scientist.

项目摘要该建议详细介绍了一项为期5年的职业发展培训计划，旨在开发特定于患者诱导多能干细胞（IPSC）模型系统研究肺泡上皮2（AT2）细胞的作用肺纤维化（PF）开始时功能障碍。现在越来越多的文献暗示了肺泡上皮功能障碍是在导致下游成纤维细胞激活的事件中发挥作用的作用各种间质性肺疾病（ILD）综合征的纤维化，包括成人特发性PF（IPF）和儿童期 ILD（儿童）。但是，如果不访问患者特定的人类上皮 - 间质模型系统，是测试AT2细胞功能障碍如何导致人类疾病的假设的有限选择。概述提案建立在最近由候选人开发和出版的体外人类模型系统上了解最常见疾病的背景下AT2细胞功能障碍的机制相关的SFTPC变体（SFTPCI73T）导致PF。通过研究AT2细胞功能障碍确定的机制使用体外IPSC衍生的模型将在SFTPCI73T突变小鼠中进一步验证。更具体地说，该提案的目的是：1）研究AT2细胞功能障碍的作用和下游的后果通过利用一种新型的人类患者特异性IPSC在体外引起纤维化级联的上皮功能障碍上皮间质重组模型系统，2）检验AT2细胞内部扰动的假设以蛋白质的缺陷和代谢重编程为特征，导致AT2至AT1细胞受损分化，炎症激活和纤维源性间充质激活，3）识别可药的通过测试新方法来恢复AT2细胞蛋白质和线粒体的新方法，用于新型PF疗法的途径功能。要开发的模型系统和要揭示的致病机制都可能是可以推广到广泛的PF表型，为家族和零星的PF疗法。 Alysandratos博士从肺，过敏，睡眠的分裂中有80％的保护时间＆重症监护医学和波士顿大学医学系。他的导师Darrell Kotton博士在再生医学中心（CREM）是干细胞生物学的国际专家，重点是应用干细胞建模和了解肺发育和疾病，使他非常适合此职业发展奖的重点是PF的IPSC模型系统。一个非凡的科学咨询团队成员都仔细组装了他们的特定专业知识，以提供补充指导。提出了一个详细的培训计划，其中包括指导研究，教学课程，会议上的演讲，以及完成研究的时间表，手稿的准备和未来R01应用程序。该提案完成后，候选人将开发必要的成功过渡到独立医师科学家的专业知识。