Role of alveolar epithelial cell-derived cellular communication network factor 2 (CCN2) in alveologenesis and bronchopulmonary dysplasia

肺泡上皮细胞源性细胞通讯网络因子 2 (CCN2) 在肺泡发生和支气管肺发育不良中的作用

• 批准号: 10459265
• 负责人: Deepthi Alapati
• 金额: $ 16.2万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459265
• 关键词: 3-Dimensional; Abnormal Cell; Address; Adverse effects; Affect; Alveolar; Animal Model; Attenuated; Basic Science; Bioinformatics; Biological Assay; Bronchopulmonary Dysplasia; CRISPR/Cas technology; Candidate Disease Gene; Cause of Death; Cell Communication; Cell Lineage; Cell physiology; Cells; Characteristics; Chronic lung disease; Clinical; Coculture Techniques; Communication; Complex; DNA; Data Set; Disease; Endothelial Cells; Endothelium; Environment; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Extracellular Matrix; Fibroblasts; Future; Gene Expression; Genes; Genetic; Goals; Hyperoxia; Impairment; In Vitro; Infant; Integrins; International; Knock-out; Knockout Mice; Label; Laboratories; Lead; Life; Lung; Lung diseases; Master' s Degree; Mediating; Mentors; Mentorship; Mesenchymal; Modeling; Modification; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Neonatal; Neurodevelopmental Impairment; Outcome; Pathologic Processes; Pathway interactions; Pediatric Hospitals; Pennsylvania; Phenotype; Premature Infant; Prevention; Prevention therapy; Production; Productivity; Proteins; Rattus; Reagent; Repression; Research; Research Personnel; Research Proposals; Resources; Role; Route; Scientist; Signal Transduction; System; Technology; Therapeutic; Time; Training; Training Programs; Transgenic Organisms; Translational Research; Universities; Vascularization; Wild Type Mouse; alveolar epithelium; antagonist; base; career; cell type; clinical care; collaborative environment; combinatorial; effective therapy; experience; experimental study; hospital readmission; hyperoxia induced lung injury; improved; in utero; innovation; insight; knock-down; lung development; lung injury; lung regeneration; lung repair; mortality; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; postnatal; prevent; response; selective expression; single-cell RNA sequencing; skills; spatiotemporal; targeted treatment; therapeutic genome editing; tool

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year training program to provide Dr. Deepthi Alapati, MD, MS, Attending Neonatologist at Nemours AI duPont Hospital for Children with the mentorship, training and research experience required to become an independent clinician scientist and a leader in neonatal lung disease research. She has received a Master’s degree in Translational Research from University of Pennsylvania. Candidate’s long-term career goal is to develop novel therapies to promote lung repair and regeneration for treatment of neonatal lung diseases such as bronchopulmonary dysplasia (BPD). To achieve these goals, she will be mentored by a team of internationally recognized experts in pulmonary basic science research from Nemours and University of Pennsylvania with whom she has a proven track record of successful mentorship and productivity. She will undergo a rigorous didactics and hands-on training program to acquire expertise in elucidating pulmonary cell-specific molecular mechanisms within the lung microenvironment using complex genetic mouse models and 3D co-culture systems; application of gene editing technologies as a mechanistic and therapeutic tool to modulate candidate genes in complex lung diseases such as BPD; and expertise in advanced bioinformatics. Her research will focus on (1) elucidating the function of Cellular communication network factor 2 (Ccn2) in alveolar epithelial cells (AEC) during alveologenesis and (2) evaluating whether modulating Ccn2 expression in AEC will improve a hyperoxia-induced BPD phenotype. This research proposal is built upon candidate’s preliminary research that demonstrates an important causative role for Ccn2 in severe BPD and the therapeutic potential of CRISPR-Cas9 gene editing technology to manipulate disease causing genes expressed in the developing pulmonary epithelium. BPD is the most common cause of death, severe neurodevelopmental impairment, and hospital readmissions in preterm infants. In spite of advances in clinical care, clinical efforts to prevent and treat BPD have been largely unsuccessful. As the cell type most exposed to the external environment, AEC have emerged as a central focus in many lung diseases, including BPD. Moreover, AEC can be directly targeted by therapeutic agents delivered through intra-amniotic, intra-nasal and intra-tracheal routes. Thus, a better understanding of mechanisms in AEC that drive alveologenesis during normal lung development and in response to early postnatal lung injury, would pave path for targeted therapies for severe BPD. By precisely examining the spatial and temporal function of Ccn2 in AEC during alveologenesis and early postnatal lung injury induced by hyperoxia, this study will provide novel mechanistic insights into its role in regulating alveologenesis and lead to novel therapies targeted at AEC-derived Ccn2 for the prevention and treatment of severe BPD. Candidate has access to all required technical, laboratory and intellectual resources in an ideal collaborative environment for successfully conducting her research and pave the path to develop as an independent investigator.

项目总结/摘要 本提案描述了一个为期5年的培训计划，为Deepthi Alapati博士，医学博士，理学硕士，主治医师 Nemours AI duPont儿童医院的新生儿医生，提供指导，培训和研究 成为一名独立的临床科学家和新生儿肺部疾病的领导者所需的经验 research.她获得了宾夕法尼亚大学翻译研究硕士学位。 候选人的长期职业目标是开发新的疗法，以促进肺修复和再生， 治疗新生儿肺部疾病，如支气管肺发育不良（BPD）。为了实现这些目标，她 将由国际公认的肺基础科学研究专家团队指导， Nemours和宾夕法尼亚大学，她与他们有成功的指导记录 和生产力。她将接受严格的教学和实践培训计划，以获得专业知识， 使用复合物阐明肺微环境中的肺细胞特异性分子机制 遗传小鼠模型和3D共培养系统;基因编辑技术作为一种机制的应用 和治疗工具，以调节复杂肺部疾病（如BPD）的候选基因;以及 先进的生物信息学她的研究将集中在（1）阐明细胞通信的功能 肺泡上皮细胞（AEC）中的网络因子2（Ccn 2）和（2）评估是否 调节AEC中的Ccn 2表达将改善高氧诱导的BPD表型。本研究提案 是建立在候选人的初步研究，证明了一个重要的致病作用，CCN 2在严重的 BPD和CRISPR-Cas9基因编辑技术的治疗潜力，以操纵引起疾病的 在发育中的肺上皮中表达的基因。BPD是最常见的死亡原因， 神经发育障碍和早产儿再次入院。尽管在临床上取得了进展， 尽管如此，预防和治疗BPD的临床努力在很大程度上是不成功的。作为最容易暴露于 由于外部环境的影响，AEC已成为许多肺部疾病（包括BPD）的中心焦点。 此外，AEC可以被通过羊膜内、鼻内和皮下递送的治疗剂直接靶向。 气管内途径。因此，更好地了解AEC中驱动肺泡发生的机制， 正常的肺发育和对出生后早期肺损伤的反应，将为靶向治疗铺平道路 严重的BPD通过精确检测Ccn 2在AEC中的时空功能， 本研究为高氧诱导新生儿早期肺损伤提供了新的机制， 深入了解其在调节肺泡发生中的作用，并导致靶向AEC衍生的Ccn 2的新疗法， 严重BPD的防治。候选人有权获得所有必要的技术，实验室和 在理想的合作环境中，她成功地进行了研究和铺路， 成为独立调查员的道路