Wnt-mediated epithelial-endothelial crosstalk in the generation and regeneration of the lung alveolus

Wnt介导的上皮-内皮串扰在肺泡生成和再生中的作用

• 批准号: 10326831
• 负责人: David Brian Frank
• 金额: $ 15.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-19 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326831
• 关键词: AGTR2 gene; Address; Advisory Committees; Alveolar; Alveolus; Appointment; Area; Biology; Blood Vessels; Blood capillaries; Bronchopulmonary Dysplasia; Cardiopulmonary; Cardiovascular system; Caring; Cell Cycle; Cells; Characteristics; Childhood; Clonal Expansion; Core Facility; Data; Development; Disease; Distal; Doctor of Philosophy; Endothelial Cells; Endothelium; Ensure; Environment; Epithelial; Epithelial Cells; Exhibits; Exposure to; Extracellular Matrix; Foundations; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Growth; In Vitro; Injury; Institution; Knock-in; Laboratories; Learning; Ligands; Light; Lung; Lung diseases; Mediating; Mentors; Mentorship; Modeling; Natural regeneration; Neonatal; Neonatal Hyperoxic Injury; Organoids; Pathway interactions; Pediatric Hospitals; Pediatric Research; Pediatrics; Philadelphia; Physicians; Play; Population; Premature Infant; Process; Production; Program Development; Pulmonary alveolar structure; Regulation; Reporting; Research; Research Personnel; Resources; Role; Scientist; System; Training; Training Programs; Transgenes; Vascular regeneration; Vocational Guidance; WNT Signaling Pathway; Work; alveolar epithelium; arteriole; body system; career; cellular targeting; epithelial stem cell; epithelium regeneration; genetic manipulation; improved; in vivo; injured; insight; instructor; lung development; mouse model; neonatal injury; neonatal lung injury; new therapeutic target; novel; pediatric cardiologist; preterm newborn; self-renewal; skills; stem cell population; stem cell self renewal; stem cells; targeted treatment; tool; transcriptome

ABSTRACT: The proposal in this application outlines a five-year training program for the development of a career as a physician-scientist in cardiopulmonary biology. The candidate is an Instructor of Pediatrics and a pediatric cardiologist at the Children’s Hospital of Philadelphia. The proposed research will be carried out under the mentorship of Dr. Edward E. Morrisey, Ph.D., a leader in the field of cardiopulmonary development. Dr. Morrisey has trained numerous young investigators including several physician-scientists who currently hold academic appointments. An advisory committee has been assembled to provide expertise in pulmonary and cardiovascular biology in addition to career guidance from well-established to newly appointed independent investigators. The research environment has been carefully selected to include exposure to two institutions allowing access to extensive resources, core facilities, and intellectual guidance. In addition, the candidate will be participating in didactic courses and numerous professional development seminars to help ensure adequate training for independence. Together, this provides a unique and ideal environment for the candidate to develop the skills to transition to an independent physician-scientist in the cardiopulmonary field. I have identified a subpopulation of Wnt signaling-responsive type 2 alveolar epithelial cells (AT2s), called Axin2+ AT2s or AT2sAxin2, which exhibit enhanced stem cell characteristics during alveologenesis (Frank DB et al. Cell Reports. 2016 Nov 22;17(9):2312-2325). In addition, the transcriptome of Axin2 AT2s are highly enriched for genes that are essential for vascular development and extracellular matrix production and interactions. The goal of this proposal is to not only further characterize this progenitor cell population in the alveolus but also examine the mechanism by which it orchestrates alveolar epithelial and endothelial growth during generation and regeneration of the alveolus. Therefore, the proposal will address these processes with two overriding aims: 1) Examine the regulation of alveolar epithelial cell self-renewal by Wnt ligand secretion; and 2) Identify and delineate the role of Wnt signaling and Wnt signaling-responsive alveolar progenitor cell populations in the epithelial-vascular niche of the developing and regenerating alveolus. ! The training program and research proposed in this application will provide critical tools, skills, and scientific expertise to become a physician-scientist in the pediatric cardiopulmonary field, a relatively understudied and underfunded area of pediatric research. There is no cure for pediatric PH and developmental lung diseases such as BPD. Thus, the identification and characterization of alveolar epithelial progenitor or stem cells could provide novel targets for therapy and lung growth.

摘要： 本申请中的建议概述了一个为期五年的培训计划，以发展职业生涯， 心肺生物学的医生兼科学家候选人是儿科讲师和儿科 费城儿童医院的心脏病专家。建议的研究将在 爱德华·E博士的指导。莫里西博士，心肺发展领域的领导者。博士 Morrisey培训了许多年轻的研究人员，包括几位目前持有 学术任命。一个咨询委员会已经成立，以提供肺和 心血管生物学除了职业指导，从完善的新任命的独立 investigators.研究环境经过精心挑选，包括接触两个机构 允许访问广泛的资源，核心设施和智力指导。此外，候选人将 参加教学课程和许多专业发展研讨会，以帮助确保充分的 独立训练。这为候选人提供了一个独特而理想的环境， 发展技能，过渡到一个独立的医生，科学家在心肺领域。 我已经确定了Wnt信号应答2型肺泡上皮细胞（AT 2）的亚群，称为 Axin 2 + AT 2s或AT 2sAxin 2，其在肺泡发生期间表现出增强的干细胞特征（Frank DB 等Cell Reports. 2016年11月22日;17（9）：2312-2325）。此外，Axin 2 AT 2的转录组高度表达于细胞中。 富含血管发育和细胞外基质产生所必需的基因， 交互.该提议的目标是不仅进一步表征在细胞中的该祖细胞群， 肺泡，但也检查其协调肺泡上皮和内皮生长的机制 在肺泡的生成和再生过程中。因此，该提案将涉及这些进程 有两个主要目的：1）检测Wnt配体对肺泡上皮细胞自我更新的调节 2）识别和描述Wnt信号传导和Wnt信号应答性肺泡上皮细胞的作用。 在发育和再生肺泡的上皮-血管龛中的祖细胞群。 ! 本申请中提出的培训计划和研究将提供关键的工具，技能和科学知识。 专业知识，成为一个医生，科学家在儿科心肺领域，一个相对欠研究， 资金不足的儿科研究领域儿童PH和发育性肺病无法治愈 例如BPD。因此，肺泡上皮祖细胞或干细胞的鉴定和表征可以 为治疗和肺生长提供新的靶点。

项目成果

Defining the spatial landscape of KRAS mutated congenital pulmonary airway malformations: a distinct entity with a spectrum of histopathologic features.

• DOI: 10.1038/s41379-022-01129-0
• 发表时间: 2022-12
• 期刊: MODERN PATHOLOGY
• 影响因子: 7.5
• 作者: Nelson, Nya D.;Xu, Feng;Chandrasekaran, Prashant;Litzky, Leslie A.;Peranteau, William H.;Frank, David B.;Li, Marilyn;Pogoriler, Jennifer
• 通讯作者: Pogoriler, Jennifer

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.

• DOI: 10.1038/s41467-021-24443-8
• 发表时间: 2021-07-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bose SK;White BM;Kashyap MV;Dave A;De Bie FR;Li H;Singh K;Menon P;Wang T;Teerdhala S;Swaminathan V;Hartman HA;Jayachandran S;Chandrasekaran P;Musunuru K;Jain R;Frank DB;Zoltick P;Peranteau WH
• 通讯作者: Peranteau WH

Hedgehog and WNT Signaling Hubs in Tracheal Morphogenesis.

Hedgehog 和 WNT 信号中枢在气管形态发生中的作用。

• DOI: 10.1164/rccm.201907-1285ed
• 发表时间: 2019
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Frank,DavidB;Morrisey,EdwardE
• 通讯作者: Morrisey,EdwardE

Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes.

• DOI: 10.1016/j.stem.2020.12.016
• 发表时间: 2021-05-06
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Shah PP;Lv W;Rhoades JH;Poleshko A;Abbey D;Caporizzo MA;Linares-Saldana R;Heffler JG;Sayed N;Thomas D;Wang Q;Stanton LJ;Bedi K;Morley MP;Cappola TP;Owens AT;Margulies KB;Frank DB;Wu JC;Rader DJ;Yang W;Prosser BL;Musunuru K;Jain R
• 通讯作者: Jain R