Transcriptional Regulation of Endothelial Cells after Neonatal Lung Injury

新生儿肺损伤后内皮细胞的转录调控

基本信息

批准号：
10661242
负责人：
Vladimir Kalinichenko
金额：
$ 67.41万
依托单位：
UNIVERSITY OF ARIZONA
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：
2018-04-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661242
关键词：
Acceleration Affect Agreement Airway Disease Alveolar Alveolar capillary dysplasia with misalignment of pulmonary veins Animals Blood Vessels Blood capillaries Bronchopulmonary Dysplasia Cell Therapy Cell Transplantation Cells Childhood Chimera organism Chromatin Chronic Circulation Complication Congenital diaphragmatic hernia Critical Care Disease Progression Donor person Endothelial Cells Endothelium Engraftment Enhancers Environment Exhibits Exposure to FOXF1 gene Future Gases Gene Delivery Genes Growth Human Hyperoxia Impairment In Vitro Infant Injury Laboratories Life Lung Lung diseases Modeling Morbidity - disease rate Mus Natural regeneration Neonatal Neonatal Hyperoxic Injury Notch Signaling Pathway Oxygen PECAM1 gene PTPRC gene Pathologic Patients Plasmids Pregnancy Premature Birth Premature Infant Proliferating Pulmonary Circulation Pulmonary Hypertension Rattus Resolution Respiratory Insufficiency Respiratory physiology Right Ventricular Hypertrophy STAT3 gene Severity of illness Stat3 protein Structure Testing Therapeutic Transcriptional Regulation Transplantation Tube Vascular remodeling angiogenesis density directed differentiation embryonic stem cell endothelial regeneration endothelial repair endothelial stem cell experience gene therapy improved in vivo injured innovation lung injury lung microvascular endothelial cells lung regeneration mortality mouse model nanoparticle nanoparticle delivery neonatal injury neonatal lung injury novel plasmid DNA postnatal preclinical study premature preservation pressure prevent progenitor protein protein interaction pulmonary function recruit repaired stem cells supplemental oxygen therapeutic nanoparticles transcription factor vascular factor vector ventilation

项目摘要

PROJECT SUMMARY. Advances in neonatal critical care have greatly improved the survival of preterm infants but the long-term complications of prematurity, including Bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. After premature birth, transition of the lung to a non-aqueous environment appears sufficient to disrupt subsequent alveolar growth and the attendant vascular structures required for effective gas exchange. This is further exacerbated when the preterm lung is exposed to supplemental oxygen and positive pressure ventilation. Irreversible loss of alveolar capillaries and vascular remodeling after oxygen exposure cause pulmonary hypertension (PH) seen in patients with severe BPD (BPD-PH). There is an urgent need for innovative therapeutic approaches to stimulate neonatal lung angiogenesis and preserve respiratory function in BPD-PH infants. My laboratory recently created PEI600-MA5/PEG-OA/Cho nanoparticles that can deliver non-integrating expression plasmids with pro-angiogenic genes into pulmonary microvascular endothelial cells with the purpose of stimulating neonatal lung angiogenesis. We also identified a specialized subpopulation of pulmonary endothelial progenitor cells (EPCs), FOXF1+ EPCs, that are a subset of recently discovered general capillary cells (gCAPs). Transplantation of FOXF1+ gCAPs increased neonatal lung angiogenesis and alveolarization in mice with congenital deficiency of alveolar capillaries. We propose to test the hypothesis that increasing neonatal lung angiogenesis via the nanoparticle FOXF1 gene therapy or the FOXF1+ gCAP cell transplantation will prevent PH and improve lung function in mouse and rat models of BPD- PH. In Aim 1, we will determine whether the nanoparticle FOXF1 gene therapy has a long-term beneficial effect in BPH-PH by preventing PH and right ventricular (RV) hypertrophy, and accelerating lung regeneration after neonatal hyperoxic lung injury. We will also identify novel downstream targets of FOXF1 in regenerating endothelial cells and test whether FOXF1 recruits STAT3 to the chromatin to activate endothelial enhancers. Our studies will determine if the FOXF1-STAT3 protein-protein interactions are required for lung regeneration in BPH-PH models. In Aim 2, we will determine whether transplantation of donor FOXF1+ gCAPs has a long- term beneficial effect by preventing PH and RV hypertrophy in mouse model of BPH-PH. We will also test requirements of the DLL4/NOTCH signaling pathway for the ability of donor FOXF1+ gCAPs to stimulate proliferation and tube formation in recipient endothelial cells during lung regeneration after hyperoxic injury. Finally, we will produce mouse FOXF1+ gCAPs from embryonic stem cells (ESCs) in vitro (via directed differentiation of ESCs into FOXF1+ gCAPs) and in vivo (via interspecies mouse-rat chimeras). Mouse ESC- derived FOXF1+ gCAPs will be used for cell therapy to prevent or delay PH and RV hypertrophy in mouse BPD-PH model. Altogether, the proposed preclinical studies will directly test whether endothelial delivery of the FOXF1 vector or cell therapy with FOXF1+ gCAPs have therapeutic potential in BPD-PH.

项目摘要。新生儿重症监护的进步大大提高了早产儿的生存率但早产儿的长期并发症，包括支气管肺发育不良 (BPD)，会导致晚年的死亡率和发病率。早产后，肺部转变为非水环境似乎足以破坏随后的肺泡生长和所需的伴随血管结构有效的气体交换。当早产儿肺部暴露于补充氧气时，这种情况会进一步加剧和正压通气。吸氧后肺泡毛细血管不可逆转的损失和血管重塑暴露会导致严重 BPD (BPD-PH) 患者的肺动脉高压 (PH)。有紧急情况需要创新的治疗方法来刺激新生儿肺血管生成并保护呼吸 BPD-PH 婴儿的功能。我的实验室最近创建了 PEI600-MA5/PEG-OA/Cho 纳米颗粒，可以将带有促血管生成基因的非整合表达质粒递送至肺微血管中内皮细胞，目的是刺激新生儿肺血管生成。我们还专门确定了肺内皮祖细胞 (EPC) 亚群，FOXF1+ EPC，是最近发现了普通毛细血管细胞（gCAP）。 FOXF1+ gCAP 移植可增加新生儿肺功能先天性肺泡毛细血管缺陷小鼠的血管生成和肺泡化。我们建议测试假设通过纳米颗粒 FOXF1 基因治疗或 FOXF1+ gCAP 细胞移植将预防 BPD 小鼠和大鼠模型中的 PH 并改善肺功能 PH值。在目标 1 中，我们将确定纳米颗粒 FOXF1 基因疗法是否具有长期有益效果通过预防 PH 和右心室 (RV) 肥大以及加速肺再生来治疗 BPH-PH 新生儿高氧性肺损伤后。我们还将确定 FOXF1 在再生中的新下游靶标内皮细胞并测试 FOXF1 是否将 STAT3 招募到染色质以激活内皮增强子。我们的研究将确定 FOXF1-STAT3 蛋白质-蛋白质相互作用是否是肺再生所必需的在 BPH-PH 模型中。在目标 2 中，我们将确定供体 FOXF1+ gCAP 的移植是否具有长期效果通过预防 BPH-PH 小鼠模型中的 PH 和 RV 肥大而产生长期有益效果。我们也会测试 DLL4/NOTCH 信号通路对供体 FOXF1+ gCAP 刺激能力的要求高氧损伤后肺再生过程中受体内皮细胞的增殖和管形成。最后，我们将在体外从胚胎干细胞 (ESC) 产生小鼠 FOXF1+ gCAP（通过定向 ESC 分化为 FOXF1+ gCAP）和体内（通过种间小鼠-大鼠嵌合体）。小鼠ESC- 衍生的 FOXF1+ gCAP 将用于细胞疗法，以预防或延缓小鼠 PH 和 RV 肥大 BPD-PH 模型。总而言之，拟议的临床前研究将直接测试内皮传递是否 FOXF1 载体或使用 FOXF1+ gCAP 的细胞疗法在 BPD-PH 中具有治疗潜力。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation.

迷走神经-巨噬细胞-肝细胞连接通过肝脏 FoxM1 激活促进损伤后肝脏再生和全身存活。

DOI：
发表时间：
2018
期刊：
影响因子：
16.6
作者：
Izumi, Tomohito;Imai, Junta;Yamamoto, Junpei;Kawana, Yohei;Endo, Akira;Sugawara, Hiroto;Kohata, Masato;Asai, Yoichiro;Takahashi, Kei;Kodama, Shinjiro;Kaneko, Keizo;Gao, Junhong;Uno, Kenji;Sawada, Shojiro;Kalinichenko, Vladimir V;Ishigaki, Y
通讯作者：
Ishigaki, Y

FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.

FOXF1 通过阻止肌成纤维细胞中的 CDH2-CDH11 钙粘蛋白开关来抑制肺纤维化。

DOI：
发表时间：
2018-04-10
期刊：
影响因子：
8.8
作者：
Black, Markaisa;Milewski, David;Le, Tien;Ren, Xiaomeng;Xu, Yan;Kalinichenko, Vladimir V;Kalin, Tanya V
通讯作者：
Kalin, Tanya V

The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia.

S52F FOXF1 突变抑制 STAT3 信号传导并导致肺泡毛细血管发育不良。

DOI：
发表时间：
2019-10-15
期刊：
影响因子：
24.7
作者：
Pradhan, Arun;Dunn, Andrew;Ustiyan, Vladimir;Bolte, Craig;Wang, Guolun;Whitsett, Jeffrey A;Zhang, Yufang;Porollo, Alexey;Hu, Yueh;Xiao, Rui;Szafranski, Przemyslaw;Shi, Donglu;Stankiewicz, Pawel;Kalin, Tanya V;Kalinichenko, Vladimir V
通讯作者：
Kalinichenko, Vladimir V

The Forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis.

Forkhead box F1 转录因子在肝纤维化过程中抑制胶原沉积和肌成纤维细胞的积累。

DOI：
发表时间：
2019-02-11
期刊：
影响因子：
2.4
作者：
Flood, Hannah M;Bolte, Craig;Dasgupta, Nupur;Sharma, Akanksha;Zhang, Yufang;Gandhi, Chandrashekhar R;Kalin, Tanya V;Kalinichenko, Vladimir V
通讯作者：
Kalinichenko, Vladimir V

Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT+ Endothelial Progenitor Cells.

出生后肺泡发生依赖于 c-KIT 内皮祖细胞中的 FOXF1 信号传导。

DOI：
发表时间：
2019-11-01
期刊：
影响因子：
24.7
作者：
Ren, Xiaomeng;Ustiyan, Vladimir;Guo, Minzhe;Wang, Guolun;Bolte, Craig;Zhang, Yufang;Xu, Yan;Whitsett, Jeffrey A;Kalin, Tanya V;Kalinichenko, Vladimir V
通讯作者：
Kalinichenko, Vladimir V