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

基本信息

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
项目类别：
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

项目摘要

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：本申请中的提案概述了一个为期五年的职业发展培训计划心肺生物学的医师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拟议的研究将在以下项目下进行。心肺发育领域的领军人物爱德华·E·莫里西 (Edward E. Morrisey) 博士的指导。莫里西培训了许多年轻的研究人员，其中包括几位目前持有学术任命已成立，以提供肺和疾病方面的专业知识。心血管生物学以及从成熟到新任命的独立职业指导研究环境经过精心挑选，包括接触两个机构。允许获得广泛的资源、核心设施和智力指导。参加教学课程和众多专业发展研讨会，以帮助确保足够的总之，这为候选人提供了一个独特且理想的环境。培养成为心肺领域独立医师科学家的技能。我发现了一个 Wnt 信号反应型 2 型肺泡上皮细胞 (AT2) 亚群，称为 Axin2+ AT2s 或 AT2sAxin2，在肺泡形成过程中表现出增强的干细胞特征（Frank DB 等人，2016 年 11 月 22 日；17(9)：2312-2325）。富含对血管发育和细胞外基质产生至关重要的基因该提案的目标不仅是进一步表征该祖细胞群的特征。肺泡，还检查其协调肺泡上皮和内皮生长的机制因此，该提案将解决这些过程。有两个首要目标：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 信号反应性肺泡的作用发育和再生肺泡的上皮血管微环境中的祖细胞群。！本申请中提出的培训计划和研究将提供关键的工具、技能和科学成为儿科心肺领域的医师科学家的专业知识，这是一个相对不足的研究和儿科研究资金不足，目前尚无法治愈儿科肺结核和发育性肺病。因此，肺泡上皮祖细胞或干细胞的鉴定和表征可以。为治疗和肺部生长提供新的靶点。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Paradigms that define lung epithelial progenitor cell fate in development and regeneration.

定义肺上皮祖细胞发育和再生命运的范例。

DOI：
发表时间：
2019-12
期刊：
影响因子：
1.4
作者：
Sivakumar, Aravind;Frank, David B
通讯作者：
Frank, David B

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

致病性 LMNA 变异会破坏心脏层-染色质相互作用并解除对替代命运基因的抑制。

DOI：
发表时间：
2021-05-06
期刊：
影响因子：
23.9
作者：
Shah, Parisha P;Lv, Wenjian;Rhoades, Joshua H;Poleshko, Andrey;Abbey, Deepti;Caporizzo, Matthew A;Linares;Heffler, Julie G;Sayed, Nazish;Thomas, Dilip;Wang, Qiaohong;Stanton, Liam J;Bedi, Kenneth;Morley, Michael P;Cappola, T
通讯作者：
Cappola, T

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

SOX17 在肺动脉高压中性别、转录和代谢的交叉点。

DOI：
发表时间：
2023-04-15
期刊：
影响因子：
24.7
作者：
Lin, Susan M;Frank, David B
通讯作者：
Frank, David B

The in vivo genetic program of murine primordial lung epithelial progenitors.

小鼠原始肺上皮祖细胞的体内遗传程序。

DOI：
发表时间：
2020-01-31
期刊：
影响因子：
16.6
作者：
Ikonomou, Laertis;Herriges, Michael J;Lewandowski, Sara L;Marsland 3rd, Robert;Villacorta;Caballero, Ignacio S;Frank, David B;Sanghrajka, Reeti M;Dame, Keri;Kańduła, Maciej M;Hicks;Lawton, Matthew L;Christodoulou
通讯作者：
Christodoulou

Dynamic Hippo pathway activity underlies mesenchymal differentiation during lung alveolar morphogenesis.

动态 Hippo 通路活性是肺泡形态发生过程中间充质分化的基础。

DOI：
发表时间：
2024-04-15
期刊：
影响因子：
0
作者：
Chaudhry, Fatima N;Michki, Nigel S;Shirmer, Dain L;McGrath;Young, Lisa R;Frank, David B;Zepp, Jarod A
通讯作者：
Zepp, Jarod A