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

Molecular regulation of cell fate and progenitor function in the distal human respiratory airways

人类远端呼吸道细胞命运和祖细胞功能的分子调控

基本信息

批准号：
10427894
负责人：
Maria Ciocca Basil
金额：
$ 16.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427894
关键词：
Address Advisory Committees Affect Alveolar Area Award Bioinformatics Cell Fate Control Cell Maintenance Cell physiology Cells Cellular Assay Cellular biology Chromatin Chronic Obstructive Pulmonary Disease Chronic lung disease Clinical Communities Critical Care Data Data Analyses Development Plans Disease Distal Doctor of Philosophy Epigenetic Process Epithelial Epithelial Cells Fellowship Genes Genetic Transcription Genomics Goals Health Human Injury Institution International Knock-out Knowledge Lead Lung Maintenance Mentors Molecular Molecular and Cellular Biology Morbidity - disease rate Mus Natural regeneration Oranges Organ Pathogenesis Pathway interactions Pennsylvania Population Regulation Research Research Personnel Resources Respiratory Disease Respiratory physiology Role SOX4 gene Scientist Secretory Cell Signal Transduction Site Structure Structure of parenchyma of lung Structure of respiratory bronchiole Techniques Testing Therapeutic Training Transcriptional Regulation Transposase Universities University Hospitals Work airway epithelium alveolar epithelium career cell type chronic respiratory disease clinically relevant epigenomics gene regulatory network genomic data healing high resolution imaging human embryonic stem cell insight lung injury lung regeneration lung repair mortality mouse model next generation sequencing notch protein novel progenitor programs repaired respiratory response to injury self-renewal skills small airways disease stem cell function stem cell model stem cells transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year training plan for the development of an independent research career focused on the role of the distal airway epithelium in human lung injury and regeneration. Specifically, the applicant strives to understand the regulation of a novel human specific secretory population called respiratory airway secretory cells (RASCs), which can act as progenitors for alveolar type 2 (AT2) cells, and understand how this population is altered in Chronic Obstructive Pulmonary Disease (COPD). The applicant is in her final year of Pulmonary and Critical Care fellowship at the Hospital of the University of Pennsylvania with previous PhD training in cellular and molecular biology with a focus on cell fate regulation. The goals of this award are to refine and develop skills that will be necessary for a successful career as an independent investigator including expertise in epigenomics, mammalian gene editing, and advanced bioinformatic analysis. The mentor for this award is Dr. Edward Morrisey, an internationally renowned expert in lung regeneration and repair with an outstanding and expansive training record. Furthermore, an advisory committee of complementary and diverse scientists has been assembled to provide breadth and depth to the training plan. The applicant will benefit from the unparalleled mentoring, resources and scientific community at the University of Pennsylvania and the unreserved support of her institution. The aims of this proposal are focused on expanding our knowledge of an understudied region of the human lung, the respiratory bronchioles. Respiratory bronchioles are absent in mouse and hence their role in lung injury, regeneration and repair is essentially unknown and often over-looked. Recent data demonstrate that respiratory bronchioles are a site of injury in COPD, highlighting the need to understand the molecular regulation and function of cell populations within this niche. This project will examine the regulation of a novel cell type recently identified in the human respiratory bronchioles, RASCs. RASCs can serve as progenitors for AT2 cells, and are transcriptionally altered in COPD, suggesting that their function could be altered in, and contribute to, the pathogenesis of this highly prevalent disease. This highlights the scientific need to investigate this cell type and its response to injury. Successful completion of these proposed studies will address the central hypothesis that the cell fate and progenitor function of RASCs is regulated through a combination of Notch signaling and the transcription factor SOX4, and that this progenitor function is altered in COPD. This will be accomplished through multiple techniques including human embryonic stem cell modeling, next-generation sequencing, and advanced epigenetic analysis of primary human lung tissue. These studies will provide significant insight into a novel lung progenitor cell and have a high potential for therapeutic impact in COPD and lung regeneration more broadly.

项目总结/文摘