Role of Senescent Cells in Radiation-induced Pulmonary Fibrosis
衰老细胞在辐射诱发的肺纤维化中的作用
基本信息
- 批准号:9976476
- 负责人:
- 金额:$ 37.67万
- 依托单位:
- 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:2018-07-20 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAlveolarAntineoplastic AgentsAreaAutomobile DrivingBCL2 geneBleomycinBlood PlateletsCancer PatientCardiovascular DiseasesCell AgingCell physiologyCellsChestChronicDefectDevelopmentDiseaseDose-LimitingEffectivenessEpithelialEpithelial CellsEpitheliumFailureFibrosisGanciclovirGeneticImpaired wound healingIndividualInflammationIonizing radiationLate EffectsLungMaintenanceMalignant neoplasm of lungMusNormal tissue morphologyOxidative StressPathogenesisPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhenotypePlayProcessProgressive DiseaseProtacPulmonary FibrosisPulmonary InflammationRadiationRadiation therapyReactive Oxygen SpeciesRoleSafetySimplexvirusStructureTERF2 geneTestingThymidine KinaseTissuesToxic effectTransgenic MiceUbiquitinationagedalveolar epitheliumbasedesignidiopathic pulmonary fibrosisimprovedinhibitor/antagonistinnovationirradiationlung injurylung small cell carcinomamouse modelnovelprematurepreventpromoterrepairedresponseself-renewalsenescenceskin fibrosisstem cell nichestem cellstissue injurytissue stem cellsubiquitin-protein ligasewound healing
项目摘要
PROJECT SUMMARY / ABSTRACT
This application is in response to NCI Provocative Question (PQ) 9 to test an innovative hypothesis that
senescent cells (SCs) induced by ionizing radiation (IR), particularly senescent type 2 alveolar epithelial
cells (AEC2s), are the perpetuators primarily responsible for initiating pathogenesis and driving
progression of radiation-induced pulmonary fibrosis (RIPF); therefore, clearance of SCs with a senolytic
drug that selectively kills SCs can prevent RIPF and/or delay its progression and, more importantly,
reverse existing tissue fibrosis, even after RIPF becomes a progressive disease. This hypothesis is based
on the long-term understanding of tissue fibrosis pathogenesis and the exciting new findings about the role of
SCs in pulmonary fibrosis, including RIPF. Specifically, pulmonary fibrosis is a disease caused by aberrant
wound healing responses that are presumably initiated by cellular senescence induction in AEC2s, which are
considered alveolar stem cells (ASCs). This process causes AEC2 defects in self-renewal and differentiation
and an inability to generate AECs for maintenance of the alveolar epithelial barrier and to repair damaged lung
epithelium. Senescent AEC2s also produce increased levels of reactive oxygen species and release an array of
proinflammatory and profibrotic factors, as a result of senescence-associated secretory phenotype (SASP)
expression, which may initiate and perpetuate pulmonary fibrosis development by inducing chronic oxidative
stress and inflammation and promoting abnormal repair of tissue injury. This is supported by the findings that (1)
AEC2 senescence, induced by AEC2-specific deletion of telomeric repeat-binding factor 2 (Trf2), in adult mice
causes ASC failure, provokes pulmonary inflammation and fibrotic responses, and sensitizes mice to bleomycin-
induced pulmonary fibrosis and (2) cellular senescence inhibition can prevent RIPF and delay bleomycin-induced
pulmonary fibrosis progression. Our preliminary studies showed that treatment of the thoracic irradiated mice
with ABT-263, a specific Bcl-2/xl inhibitor and a newly discovered senolytic drug by our group, almost completely
reversed RIPF, even when ABT-263 treatment was delayed until RIPF was established. To our knowledge, this
is the first study to demonstrate that RIPF can be reversed by a drug after it becomes a progressive disease.
From these novel findings, we will test our hypothesis through the following specific aims using our well-
established thoracic irradiation mouse model: (1) validate that SCs are the perpetuators primarily responsible for
initiating pathogenesis and driving progression of RIPF; (2) elucidate the mechanisms by which clearance of
SCs prevents and reverses RIPF; and (3) develop a safer and more effective senolytic drug treatment for RIPF.
RIPF is one of the most deleterious late effects of thoracic radiotherapy. Our proposed studies will lead to the
identification of the underlying mechanisms whereby IR causes pulmonary fibrosis and development of an
innovative mechanism-based therapy that can not only prevent and/or delay RIPF but also reverse RIPF.
项目摘要/摘要
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
DAOHONG ZHOU其他文献
DAOHONG ZHOU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('DAOHONG ZHOU', 18)}}的其他基金
Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis
针对 BCL-XL 的蛋白水解靶向嵌合体抑制乳腺癌转移
- 批准号:
10390383 - 财政年份:2021
- 资助金额:
$ 37.67万 - 项目类别:
Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis
针对 BCL-XL 的蛋白水解靶向嵌合体抑制乳腺癌转移
- 批准号:
10198532 - 财政年份:2021
- 资助金额:
$ 37.67万 - 项目类别:
Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis
针对 BCL-XL 的蛋白水解靶向嵌合体抑制乳腺癌转移
- 批准号:
10653814 - 财政年份:2021
- 资助金额:
$ 37.67万 - 项目类别:
Role of Senescent Cells in Radiation-induced Pulmonary Fibrosis
衰老细胞在辐射诱发的肺纤维化中的作用
- 批准号:
10226299 - 财政年份:2018
- 资助金额:
$ 37.67万 - 项目类别:
Role of Senescent Cells in Radiation-induced Pulmonary Fibrosis
衰老细胞在辐射诱发的肺纤维化中的作用
- 批准号:
10644770 - 财政年份:2018
- 资助金额:
$ 37.67万 - 项目类别:
Ionizing radiation induced hematological malignancies
电离辐射诱发的血液系统恶性肿瘤
- 批准号:
10722863 - 财政年份:2017
- 资助金额:
$ 37.67万 - 项目类别:
Ionizing radiation induced hematological malignancies
电离辐射诱发的血液系统恶性肿瘤
- 批准号:
9899947 - 财政年份:2017
- 资助金额:
$ 37.67万 - 项目类别:
Ionizing radiation induced hematological malignancies
电离辐射诱发的血液系统恶性肿瘤
- 批准号:
9216070 - 财政年份:2017
- 资助金额:
$ 37.67万 - 项目类别:
Role of p38 MAPK in HSC Self-Renewal and Radiation-Induced Bone Marrow Injury
p38 MAPK 在 HSC 自我更新和辐射诱导的骨髓损伤中的作用
- 批准号:
8072241 - 财政年份:2010
- 资助金额:
$ 37.67万 - 项目类别:
相似海外基金
Gain-of-function toxicity in alpha-1 antitrypsin deficient type 2 alveolar epithelial cells
α-1 抗胰蛋白酶缺陷型 2 型肺泡上皮细胞的功能获得毒性
- 批准号:
10751760 - 财政年份:2024
- 资助金额:
$ 37.67万 - 项目类别:
The role of alveolar macrophages and regulatory pathways in post-transplant lung inflammation.
肺泡巨噬细胞和调节途径在移植后肺部炎症中的作用。
- 批准号:
23K08315 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pilot Studies of PAX3-FOXO1 Fusions Proteins in Alveolar Rhabdomyosarcoma
PAX3-FOXO1 融合蛋白在肺泡横纹肌肉瘤中的初步研究
- 批准号:
10726763 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Mechanistic studies of the genetic contribution of desmoplakin to pulmonary fibrosis in alveolar type 2 cells
桥粒斑蛋白对肺泡2型细胞肺纤维化的遗传贡献机制研究
- 批准号:
10736228 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Utilizing induced pluripotent stem cells to study the role of alveolar type 2 cell dysfunction in pulmonary fibrosis
利用诱导多能干细胞研究肺泡2型细胞功能障碍在肺纤维化中的作用
- 批准号:
10591174 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Novel alveolar mechanisms of hypoxemia in hepatopulmonary syndrome
肝肺综合征低氧血症的新肺泡机制
- 批准号:
10718446 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Mechanical signaling through the nuclear membrane in lung alveolar health
通过核膜的机械信号传导影响肺泡健康
- 批准号:
10677169 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Injury of blood brain and alveolar-endothelial barriers caused by alcohol and electronic cigarettes via purinergic receptor signaling
酒精和电子烟通过嘌呤受体信号传导引起血脑和肺泡内皮屏障损伤
- 批准号:
10638221 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Alveolar Epithelial Cell Dysfunction Induced By Flavored E-Cigarette Aerosols
加味电子烟气雾剂引起的肺泡上皮细胞功能障碍
- 批准号:
10770080 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:
Delineating the role of let-7 microRNA on lung AT2 cell homeostasis, alveolar regeneration, and interstitial lung disease
描述let-7 microRNA对肺AT2细胞稳态、肺泡再生和间质性肺疾病的作用
- 批准号:
10634881 - 财政年份:2023
- 资助金额:
$ 37.67万 - 项目类别:














{{item.name}}会员




