Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
基本信息
- 批准号:9265926
- 负责人:
- 金额:$ 48.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-05-02 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAir SacsAlveolarAngiogenic FactorAnimal ModelAreaBlood VesselsBlood capillariesBronchopulmonary DysplasiaCell MaturationCell SurvivalComplicationDataDevelopmentDiseaseDistalEndothelial CellsEndotheliumGasesGene Expression ProfileGrowthImpairmentIn VitroInfantInflammationInjuryKnowledgeLinkLungLung diseasesMalignant NeoplasmsMediatingMediator of activation proteinMolecularMusNF-kappa BNatural regenerationNeonatalOrgan Culture TechniquesPathogenesisPathway interactionsPatientsPhenotypePhysiologicalPremature BirthProcessProteinsProteomicsRoleSurfaceTestingTherapeuticTransforming Growth FactorsTranslatingTumor AngiogenesisVascularizationWorkWound Healingalpha-Fetoproteinsangiogenesisblood vessel developmentcapillarycell motilitydensityexperimental studyin vivoinnovationloss of functionlung developmentmigrationnovelnovel therapeutic interventionpostnatalpublic health relevanceresponse to injurytargeted treatmenttranscription factor
项目摘要
DESCRIPTION (provided by applicant): Growth of the pulmonary capillaries by angiogenesis is essential for alveolarization, and disruption of pulmonary angiogenesis contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common complication of premature birth. However, the molecular pathways that orchestrate pulmonary angiogenesis during development and disease are not fully understood. This gap in knowledge continues to confound efforts to develop targeted therapies to treat lung diseases caused by impaired angiogenesis, including BPD. Nuclear factor κ-B (NFκB) is a key regulator of inflammation, and growing evidence suggests that NFκB regulates angiogenesis in wound healing in cancer. In contrast, little is known about the role of NFκB in the developing lung. We recently demonstrated that NFκB is essential for alveolarization.
NFκB is constitutively active in the neonatal, but quiescent in the adult lung, and inhibiting NFκB disrupts pulmonary angiogenesis and alveolarization in neonatal mice, but has no effect in adults. Blocking NFκB in neonatal primary pulmonary endothelial cells (PEC) impairs survival, proliferation, and in vitro angiogenesis. Activation of NFκB in the PEC corresponds to the period of angiogenesis in the developing lung, peaking at the onset of alveolarization, and decreasing to low levels by mid-alveolarization. However, the capacity for NFκB to be activated in the PEC is not intrinsic to the cell's maturation, as conditioned media obtained from early alveolar lung organ culture (EA-LCM), robustly activates NFκB and enhances migration in adult PEC. Global proteomic analysis to compare the early alveolar and adult lung secretomes identified factors secreted only by the early alveolar lung (EAL). Studies to examine the effect of neutralizing each of these proteins on the ability of the EA-LCM to promote NFκB activation and migration, allowed the identification of two putative activators of NFκB in the early alveolar lung: transforming growth factor-ß induced protein (TGFBI) and alpha-fetoprotein (AFP). Both factors are expressed in the EAL in vivo but minimally expressed in the adult lung, and both are suppressed by injuries that disrupt alveolarization. Therefore, our data suggest the overall working hypothesis that factors uniquely secreted by the EAL promote lung angiogenesis and alveolarization by activating NFκB in the pulmonary endothelium by addressing two inter-related specific aims. In Aim 1, we will examine if TGFBI and AFP secretion by the EAL induces a pro-angiogenic phenotype in the PEC via an NFκB-dependent pathway, and explore if TGFBI and AFP activate common or complementary patterns of gene expression. Aim 2 will utilize in vivo gain and loss of function strategies to determine if disrupting TGFBI- or AFP-mediated activation of NFκB impairs alveolar growth during development and injury. The successful completion of these studies will establish a novel, physiologic role for NFκB in the developing lung, and identify new angiogenic factors that can be directly translated into therapeutic strategies to promote lung growth and regeneration in diseases marked by impaired pulmonary angiogenesis.
描述(由申请方提供):通过血管生成的肺毛细血管生长对于肺泡化至关重要,并且肺血管生成的破坏有助于支气管肺发育不良(BPD)的发病机制,BPD是早产最常见的并发症。然而,在发育和疾病过程中协调肺血管生成的分子途径尚未完全了解。这种知识上的差距继续混淆了开发靶向疗法以治疗由血管生成受损引起的肺部疾病(包括BPD)的努力。核因子κ-B(NFκB)是炎症的关键调节因子,越来越多的证据表明NFκB调节癌症伤口愈合中的血管生成。相反,NFκB在肺发育中的作用知之甚少。我们最近证实NFκB对肺泡形成是必不可少的。
NFκB在新生小鼠中具有组成性活性,但在成年小鼠中处于静止状态,抑制NFκB可破坏新生小鼠的肺血管生成和肺泡化,但对成年小鼠无影响。阻断新生儿原代肺内皮细胞(PEC)中的NFκB可损害存活、增殖和体外血管生成。PEC中NFκB的激活对应于发育中肺的血管生成期,在肺泡化开始时达到峰值,并在肺泡化中期降至低水平。然而,NFκB在PEC中被激活的能力不是细胞成熟所固有的,因为从早期肺泡肺器官培养物(EA-LCM)获得的条件培养基强烈地激活NFκB并增强成体PEC中的迁移。全球蛋白质组学分析比较早期肺泡和成人肺分泌物组确定的因素分泌的早期肺泡肺(EAL)。通过研究中和这些蛋白质对EA-LCM促进NFκB活化和迁移能力的影响,鉴定了早期肺泡肺中NFκB的两种假定活化剂:转化生长因子-β诱导蛋白(TGFBI)和甲胎蛋白(AFP)。这两种因子在体内EAL中表达,但在成人肺中表达最低,并且两者都受到破坏肺泡化的损伤的抑制。因此,我们的数据表明,EAL独特分泌的因子通过激活肺内皮细胞中的NFκB促进肺血管生成和肺泡化的总体工作假设,通过解决两个相互关联的特定目标。在目的1中,我们将检测EAL分泌的TGFBI和AFP是否通过NFκ B依赖性途径诱导PEC中的促血管生成表型,并探索TGFBI和AFP是否激活共同或互补的基因表达模式。目的2将利用体内获得和丧失功能的策略来确定在发育和损伤过程中破坏TGFBI或AFP介导的NFκB活化是否损害肺泡生长。这些研究的成功完成将确立NFκB在肺发育中的新的生理作用,并确定新的血管生成因子,这些因子可直接转化为治疗策略,以促进以肺血管生成受损为标志的疾病的肺生长和再生。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Cristina Maria Alvira其他文献
Cristina Maria Alvira的其他文献
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{{ truncateString('Cristina Maria Alvira', 18)}}的其他基金
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
- 批准号:
10467727 - 财政年份:2022
- 资助金额:
$ 48.26万 - 项目类别:
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
- 批准号:
10615235 - 财政年份:2022
- 资助金额:
$ 48.26万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10678976 - 财政年份:2021
- 资助金额:
$ 48.26万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10583456 - 财政年份:2021
- 资助金额:
$ 48.26万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10211048 - 财政年份:2021
- 资助金额:
$ 48.26万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10362528 - 财政年份:2021
- 资助金额:
$ 48.26万 - 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
- 批准号:
10373975 - 财政年份:2018
- 资助金额:
$ 48.26万 - 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
- 批准号:
9893885 - 财政年份:2018
- 资助金额:
$ 48.26万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
8686276 - 财政年份:2014
- 资助金额:
$ 48.26万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
9059764 - 财政年份:2014
- 资助金额:
$ 48.26万 - 项目类别:
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