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PROTEASOME DEGRADATION OF P53 DRIVES HPS LUNG FIBROSIS

P53 的蛋白酶体降解导致 HPS 肺纤维化

基本信息

批准号：
10251009
负责人：
Freddy Romero
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251009
关键词：
26S proteasome Antioxidants Attenuated Biogenesis Bleomycin Blood Platelets Complex Data Development Disease Distal Down-Regulation Effectiveness Epithelial Epithelial Cells Exposure to Fibrosis Fostering Foundations Functional disorder Future Genes Genetic Grant Hermanski-Pudlak Syndrome Homeostasis Impairment In Vitro Injury Link Lung Lung diseases Lysosomes Mediating Modeling Molecular Mus Mutation Organ Organelles Pathogenesis Pathology Pharmacology Piebaldism Predisposition Proteins Pulmonary Fibrosis Rare Diseases Regulation Research Role Severities Sorting - Cell Movement Structure of parenchyma of lung TP53 gene Techniques Testing Therapeutic Tissues Ubiquitin Work alveolar epithelium base clathrin assembly protein AP180 clinical investigation effective therapy gain of function genetic approach human disease improved in vivo indium-bleomycin injured late endosome lung injury lysosomal proteins multicatalytic endopeptidase complex novel novel therapeutic intervention protein complex protein degradation response trafficking transcription factor ubiquitin ligase virtual wound healing

项目摘要

ABSTRACT: Hermansky-Pudlak syndrome (HPS) is a rare form of pulmonary fibrosis that results from mutations in genes that regulate the function of lysosomes and lysosomal-related organelles. Although mutations in the alveolar epithelium have been linked to the development of HPS lung fibrosis, the mechanisms by which these mutations enhance susceptibility of the lung to injury are unknown. In recent work, we uncovered a novel mechanism by which epithelial-specific HPS mutations promote fibrotic remodeling in the lung. We have found that deficiency in the AP3 protein (a known HPS gene) leads to marked reduction in expression of p53 in the alveolar epithelium by increasing ubiquitin-proteasome degradation of this protein. Further, we uncovered that expression of p53 is essential for regulating antioxidant and barrier defenses in the lung epithelium and we also found that strategies which increase p53 expression can effectively restore epithelial homeostasis and reduce fibrotic remodeling in the lungs of bleomycin-exposed AP3 deficient mice. Based on these observations, we propose the following central hypothesis regarding the pathogenesis of pulmonary fibrosis in HPS: We hypothesize that AP3 deficiency enhances susceptibility to pulmonary fibrosis by decreasing p53 expression in the distal lung epithelium, and strategies that augment p53 expression can both attenuate lung injury and reduce fibrotic remodeling to bleomycin in the HPS mouse lung. This central hypothesis will be tested in 3 Specific Aims. In Specific Aim 1, we will test the hypothesis that AP3 deficiency reduces p53 expression by enhancing ubiquitin-proteasome degradation. We will determine whether genetic and pharmacological approaches that block the degradation of p53 enhance antioxidant and epithelial barrier defenses and reduce fibrotic remodeling in the bleomycin-exposed lung. In Specific Aim 2, we will confirm that expression of p53 is critically important in maintaining antioxidant and barrier defenses in the lung by performing various in vitro and in vivo loss- and gain-of-function studies in wild-type and AP3 deficient injured and uninjured tissues. Lastly, in Specific Aim 3, we will test the hypothesis that decreased macroautophagy in the alveolar epithelium of AP3 deficient mice contributes to accumulation of the ubiquitin ligases which target p53 for degradation. We will further test whether strategies augmenting macroautophagy can reduce p53 degradation, augment anti-oxidant and epithelial barrier defenses and ameliorate bleomycin-induced fibrotic remodeling in the lung. In summary, this proposal will establish the mechanisms by which AP3 deficiency enhances susceptibility to pulmonary injury/fibrosis and lay the foundation for future clinical investigations testing whether therapeutic strategies targeting these mechanisms can attenuate the onset or progression of pulmonary fibrosis in HPS.

摘要：Hermansky-Pudlak综合征（HPS）是一种罕见的肺纤维化，调节溶酶体和溶酶体相关细胞器功能的基因突变。虽然肺泡上皮细胞中的突变与HPS肺纤维化的发生有关，这些突变增强肺对损伤的易感性的机制尚不清楚。在最近的工作中，我们发现了一种新的机制，通过这种机制，上皮特异性HPS突变促进纤维化重塑，肺我们已经发现，AP 3蛋白（一种已知的HPS基因）的缺陷导致HPS的表达显著降低。 p53在肺泡上皮细胞中的表达，通过增加这种蛋白的泛素-蛋白酶体降解。此外，我们发现p53的表达对于调节抗氧化剂和屏障防御是必不可少的。我们还发现，增加p53表达的策略可以有效地恢复肺上皮细胞，在博来霉素暴露的AP 3缺陷小鼠的肺中，基于这些观察结果，我们提出了以下关于 HPS中的肺纤维化：我们假设AP 3缺乏增加了肺纤维化的易感性通过减少远端肺上皮中p53的表达，增加p53表达的策略可以两者都能减轻HPS小鼠肺中博莱霉素的肺损伤并减少纤维化重塑。这次中央假设将在3个具体目标中进行检验。在具体目标1中，我们将检验AP 3缺乏通过增强泛素-蛋白酶体降解降低p53表达。我们将确定是否遗传阻断p53降解的药理学方法增强抗氧化剂和上皮屏障防御和减少博莱霉素暴露的肺中的纤维化重塑。在具体目标2中，我们将确认， p53的表达在维持肺中的抗氧化和屏障防御中是至关重要的，在野生型和AP 3缺陷型损伤中进行各种体外和体内功能丧失和获得研究，和未受伤的组织。最后，在具体目标3中，我们将测试减少巨自噬的假设， AP 3缺陷小鼠的肺泡上皮有助于泛素连接酶的积累， p53降解。我们将进一步测试增强巨自噬的策略是否可以减少p53 降解，增强抗氧化剂和上皮屏障防御，并改善博来霉素诱导的纤维化肺部重塑总之，该提案将建立AP3缺陷的机制，增加肺损伤/纤维化的易感性，为未来的临床研究奠定基础测试靶向这些机制的治疗策略是否可以减弱肺纤维化。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung.

DOI：
10.1186/s12931-021-01640-z
发表时间：
2021-02-08
期刊：
Respiratory research
影响因子：
5.8
作者：
Cuevas-Mora K;Roque W;Shaghaghi H;Gochuico BR;Rosas IO;Summer R;Romero F
通讯作者：
Romero F

A model of the aged lung epithelium in idiopathic pulmonary fibrosis.

DOI：
10.18632/aging.203291
发表时间：
2021-07-08
期刊：
Aging
影响因子：
0
作者：
Shaghaghi H;Cuevas-Mora K;Para R;Tran C;Roque W;Robertson MJ;Rosas IO;Summer R;Romero F
通讯作者：
Romero F

Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis.