Epithelial Protective Effects of Thyroid Hormone Signaling in Fibrosis

甲状腺激素信号传导对纤维化的上皮保护作用

• 批准号: 10307633
• 负责人: NAFTALI KAMINSKI
• 金额: $ 78.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307633
• 关键词: Acute; Address; Affect; Aging; Agonist; Anatomy; Antigens; Antioxidants; Apoptosis; Autoimmune Diseases; Autophagocytosis; Biogenesis; Biology; Bleomycin; Cardiac; Cell Survival; Cells; Characteristics; Chemical Warfare; Chronic; DNA; Deposition; Diagnosis; Disease; Dose; Epigenetic Process; Epithelial; Epithelial Cells; Exhibits; Exposure to; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Generations; Genetic Diseases; Genetically Modified Animals; Genomic Instability; Health; Homeostasis; Human; Hydrogen Peroxide; Hypothyroidism; Incidence; Injury; Interstitial Lung Diseases; Kinetics; Letters; Longitudinal cohort; Lung; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Morphology; Mus; OLFM4 gene; Oligomycins; Organ; Oxidants; Oxides; PINK1 gene; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Process; Production; Prognosis; Progressive Disease; Pulmonary Fibrosis; Radiation; Reactive Oxygen Species; Regulation; Research; Resolution; Role; Secondary to; Signal Pathway; Slice; Specimen; Structure of parenchyma of lung; System; Testing; Therapeutic; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Toxic Environmental Substances; Toxic effect; Transcription Coactivator; aerosolized; alveolar epithelium; alveolar type II cell; antifibrotic treatment; cell injury; contextual factors; end-stage organ failure; epithelial injury; experimental study; fibrotic lung; hormonal signals; idiopathic pulmonary fibrosis; improved; interest; lung injury; mitochondrial dysfunction; mortality; multiple chronic conditions; prevent; protective effect; recruit; repaired; response; response to injury; restoration; skeletal; telomere; wound healing

PROJECT SUMMARY Pulmonary fibrosis (PF) describes a condition in which the normal lung anatomy is replaced by a process of active remodeling, deposition of extracellular matrix and dramatic changes in the phenotype of both fibroblasts and alveolar epithelial cells, as a result of an abnormal wound healing process. This condition can be idiopathic, as in idiopathic pulmonary fibrosis (IPF), or secondary to genetic disorders, lung parenchyma involvement in autoimmune disorders, or to exposure to environmental toxins, chemical warfare, drugs, foreign antigens, or radiation. IPF is the most common idiopathic form of pulmonary fibrosis that affects approximately 120,000 patients in the US with a steady increase in both incidence and mortality. 40,000 patients die from IPF each year. More recently it has been proposed that many of the hallmarks of aging including genomic instability, telomere attrition, epigenetic alterations, and mitochondrial dysfunction can be considered characteristic of the fibrotic lung. Specifically, alveolar type II cells exhibit dysmorphic mitochondria, reduced energy production and increased mitochondrial reactive oxygen species. We recently discovered that administration of thyroid hormone late after bleomycin induced lung injury significantly enhanced the resolution of murine bleomycin-induced lung fibrosis. We discovered that these effects were associated with induction of PPARGC1A, a transcriptional coactivator with significant roles in regulation of metabolism, mitochondrial remodeling and mitochondrial biogenesis. This effect was accompanied by reduced apoptosis and normalized mitochondrial morphology and function in alveolar type II cells and was dependent on intact mitogeneration and mitophagy pathways. Finally, in banked plasma specimens obtained from a large, well characterized longitudinal cohort of IPF patients, we identified increased levels of circulating mitochondrial DNA that were associated with significantly increased mortality in these patients. Considering that thyroid hormone is critically important for repair after injury through activation of pro-survival and anti-oxidant signaling pathways and regulation of mitochondrial homeostasis and metabolism and that hypothyroidism is associated with unfavorable prognosis in multiple chronic conditions including IPF, we hypothesize that restoration of mitochondrial homeostasis by augmented thyroid hormone signaling could establish a viable therapeutic strategy for epithelial protection and resolution of pulmonary fibrosis. We will address this hypothesis by the following specific aims: Aim 1: To determine that thyroid hormone signaling reverses cellular injury by inducing both mitogeneration and mitophagy. Aim 2: To determine how thyroid hormone signaling induced changes in mitochondrial biology result in reduction of organ fibrosis. Aim 3: To establish the potential utility of Sobetirome, a thyromimetic drug relatively devoid of thyroid cardiac and skeletal toxicity, as an antifibrotic agent. Together these experiments will establish the mechanisms and rationale for the use of augmenting thyroid hormone signaling as an antifibrotic strategy in humans.

项目摘要 肺纤维化（PF）描述了其中正常的肺解剖结构被肺纤维化过程替代的病症。 两种成纤维细胞的活性重塑、细胞外基质沉积和表型的显著变化 和肺泡上皮细胞，作为异常伤口愈合过程的结果。这种情况可能是特发性的， 如在特发性肺纤维化（IPF）中，或继发于遗传性疾病， 自身免疫性疾病，或暴露于环境毒素，化学战，药物，外来抗原，或 辐射IPF是最常见的特发性肺纤维化形式，影响约120，000例 美国患者的发病率和死亡率均稳步上升。每年有40，000名患者死于IPF。 最近有人提出，衰老的许多标志，包括基因组的不稳定性，端粒， 磨损、表观遗传改变和线粒体功能障碍可以被认为是纤维化的特征。 肺。具体地，肺泡II型细胞表现出畸形的线粒体，减少的能量产生和 线粒体活性氧增加。我们最近发现甲状腺激素的使用 博莱霉素诱导肺损伤后晚期明显增强博莱霉素诱导小鼠肺的消退 纤维化我们发现这些效应与PPARGC 1A的诱导有关，PPARGC 1A是一种转录因子， 在调节代谢、线粒体重塑和线粒体凋亡中具有重要作用的共激活因子 生物起源。这种作用伴随着细胞凋亡减少和线粒体形态正常化， 在肺泡II型细胞的功能，并依赖于完整的有丝分裂和线粒体自噬途径。最后， 在从一个大型的、充分表征的IPF患者纵向队列中获得的库存血浆标本中，我们 确定了循环线粒体DNA水平的增加， 这些患者的死亡率。考虑到甲状腺激素对损伤后的修复至关重要， 激活促存活和抗氧化信号传导途径，调节线粒体稳态， 甲状腺功能减退症与多种慢性疾病的不良预后有关 包括特发性肺纤维化，我们假设通过增加甲状腺激素恢复线粒体稳态， 信号传导可以建立一个可行的治疗策略，用于上皮保护和肺动脉高压的解决。 纤维化我们将通过以下具体目标来解决这一假设：目标1：确定甲状腺激素 信号转导通过诱导有丝分裂和线粒体自噬来逆转细胞损伤。目标2：确定如何 甲状腺激素信号传导诱导的线粒体生物学变化导致器官纤维化减少。目标三： 为了确定Sobetirome的潜在效用，Sobetirome是一种相对缺乏甲状腺心脏和 骨骼毒性，作为抗纤维化剂。这些实验将共同建立机制和原理 用于增强甲状腺激素信号传导作为人类抗纤维化策略的用途。

项目成果

A statistical framework to identify cell types whose genetically regulated proportions are associated with complex diseases.

• DOI: 10.1371/journal.pgen.1010825
• 发表时间: 2023-07
• 期刊: PLoS genetics
• 影响因子: 4.5

Long noncoding RNA TINCR is a novel regulator of human bronchial epithelial cell differentiation state.

• DOI: 10.14814/phy2.14727
• 发表时间: 2021-03
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Omote N;Sakamoto K;Li Q;Schupp JC;Adams T;Ahangari F;Chioccioli M;DeIuliis G;Hashimoto N;Hasegawa Y;Kaminski N
• 通讯作者: Kaminski N

Somatic Mutations: The Next Frontier in Demystifying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis?

体细胞突变：揭开慢性阻塞性肺疾病和特发性肺纤维化神秘面纱的下一个前沿？

• DOI: 10.1164/rccm.202310-1774ed
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Yan,Xiting;Kaminski,Naftali
• 通讯作者: Kaminski,Naftali

microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.

• DOI: 10.1172/jci.insight.158100
• 发表时间: 2023-02-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Ahangari, Farida;Price, Nathan L.;Malik, Shipra;Chioccioli, Maurizio;Barnthaler, Thomas;Adams, Taylor S.;Kim, Jooyoung;Pradeep, Sai Pallavi;Ding, Shuizi;Cosmos Jr., Carlos;Rose, Kadi-Ann S.;McDonough, John E.;Aurelien, Nachelle R.;Ibarra, Gabriel;Omote, Norihito;Schupp, Jonas C.;DeIuliis, Giuseppe;Nunez, Julian A. Villalba;Sharma, Lokesh;Ryu, Changwan;Dela Cruz, Charles S.;Liu, Xinran;Prasse, Antje;Rosas, Ivan;Bahal, Raman;Fernandez-Hernando, Carlos;Kaminski, Naftali
• 通讯作者: Kaminski, Naftali

Alveolar Vascular Remodeling in Nonspecific Interstitial Pneumonia: Replacement of Normal Lung Capillaries with COL15A1-Positive Endothelial Cells.

非特异性间质性肺炎中的肺泡血管重塑：用 COL15A1 阳性内皮细胞替换正常肺毛细血管。

• DOI: 10.1164/rccm.202303-0544le
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Schupp,JonasC;Manning,EdwardP;Chioccioli,Maurizio;Kamp,JanC;Christian,Leonard;Ryu,Changwan;Herzog,Erica;Kühnel,MarkP;Prasse,Antje;Kaminski,Naftali;Jonigk,DannyD;Homer,RobertJ;Yale-MHH-MGHStudyGroup
• 通讯作者: Yale-MHH-MGHStudyGroup