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.

项目摘要/摘要 该提案描述了一项为期5年的培训计划，以提供Deepthi Alapati，医学博士，MS Nemours AI Dupont医院的新生儿医生接受精神，培训和研究的儿童 成为独立临床科学家和新生儿肺部疾病的领导者所需的经验 研究。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颖的疗法，以促进肺修复和再生 新生儿肺部疾病（例如支气管肺发育不良（BPD））的治疗。为了实现这些目标，她 将由国际认可的肺基础科学研究专家团队考虑 Nemours和宾夕法尼亚大学，她拥有成功的Mentalship的良好记录 和生产力。她将接受严格的教学和动手培训计划，以获取专业知识 使用复合物在肺微环境内阐明肺细胞特异性分子机制 遗传小鼠模型和3D共培养系统；基因编辑技术的应用 以及在复杂的肺部疾病（例如BPD）中调节候选基因的治疗工具；和专业知识 先进的生物信息学。她的研究将集中于（1）阐明细胞通信的功能 肺泡术期间肺泡上皮细胞（AEC）中的网络因子2（CCN2）和（2）评估是否是否评估 在AEC中调节CCN2表达将改善高氧诱导的BPD表型。这项研究建议 建立在候选人的初步研究之上，该研究表明CCN2在严重 BPD和CRISPR-CAS9基因编辑技术的治疗潜力操纵疾病 在发育中的肺上皮中表达的基因。 BPD是最常见的死亡原因，严重 神经发育障碍和早产儿的医院再入院。尽管临床进展 护理，预防和治疗BPD的临床努力在很大程度上没有成功。由于细胞类型最暴露于 外部环境AEC已成为包括BPD在内的许多肺部疾病的中心重点。 此外，AEC可以通过通过肿瘤内，鼻内和 气体内路线。这是对在AEC中的机制的更好理解，该机制在 正常的肺发育并应对早期产后肺损伤，将为靶向疗法铺平道路 对于严重的BPD。通过精确检查CCN2在AEC中的空间和临时功能 肺单术和高氧诱导的早期产后肺损伤将提供新的机械 洞悉其在调节肺单术中的作用并导致针对AEC衍生CCN2的新型疗法 严重BPD的预防和治疗。候选人可以访问所有必需的技术，实验室和 在理想的协作环境中，智力资源成功地进行了她的研究和铺路 发展为独立研究者的途径。