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.

抽象的： 该应用程序中的建议概述了为期五年的培训计划，以发展职业 心肺生物学的医师科学家。候选人是儿科和儿科的讲师 费城儿童医院的心脏病专家。拟议的研究将在 爱德华·E·莫里西（Edward E. Morrisey）博士的指导是心肺发展领域的领导者。博士 莫里西（Morrisey）培训了许多年轻调查员，包括几位身体科学家 学术任命。已经组建了一个咨询委员会，以提供肺部的专业知识 心血管生物学除了从成熟到新任命的独立的职业指导外 调查人员。已经仔细选择了研究环境，包括接触两个机构 允许获取广泛的资源，核心设施和智力指导。此外，候选人将 参加教学课程和众多的专业发展半货人，以帮助确保足够 独立培训。一起，这为候选人提供了一个独特而理想的环境 在心肺领域过渡到独立的身体科学家的技能。 我已经确定了Wnt信号响应2型肺泡上皮细胞（AT2S）的亚群，称为 AXIN2+ AT2S或AT2SAXIN2，在肺泡术期间暴露了增强的干细胞特征（Frank DB 等。细胞报告。 2016年11月22日； 17（9）：2312-2325）。另外，Axin2 AT2的转录组高度高 富含对血管发育和细胞外基质产生至关重要的基因和 互动。该提案的目的不仅是进一步描述了该祖细胞种群 肺泡，但还检查了其协调肺泡上皮和内皮生长的机制 在肺泡的产生和再生过程中。因此，该提案将解决这些过程 有两个重大目标：1）检查Wnt配体对肺泡上皮细胞自我更新的调节 分泌; 2）识别并描述Wnt信号传导和Wnt信号响应肺泡的作用 发育中和再生肺泡的上皮血管生态位中的祖细胞群体。 呢 本应用程序中提出的培训计划和研究将提供关键的工具，技能和科学 成为小儿心肺领域的身体科学家的专业知识，相对理解和 小儿研究资金不足的地区。无法治愈小儿pH和发育性肺部疾病 例如BPD。那，牙槽上皮祖细胞或干细胞的鉴定和表征可以 为治疗和肺部生长提供新的靶标。

项目成果

SOX17 at the Intersection of Sex, Transcription, and Metabolism in Pulmonary Hypertension.

• DOI: 10.1164/rccm.202302-0284ed
• 发表时间: 2023-04-15
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7

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