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.

项目概要 肺纤维化 (PF) 是指正常肺解剖结构被以下过程所取代的病症： 两种成纤维细胞的主动重塑、细胞外基质沉积和表型的巨大变化 和肺泡上皮细胞，由于伤口愈合过程异常。这种情况可能是特发性的， 如特发性肺纤维化（IPF）或继发于遗传性疾病，肺实质受累 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，影响约 120,000 人 美国患者的发病率和死亡率都在稳步上升。每年有 40,000 名患者死于 IPF。 最近有人提出，衰老的许多特征包括基因组不稳定性、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。具体来说，肺泡 II 型细胞表现出线粒体畸形、能量产生减少和 线粒体活性氧增加。我们最近发现，服用甲状腺激素 博来霉素诱导的肺损伤后晚期显着增强了小鼠博来霉素诱导的肺损伤的分辨率 纤维化。我们发现这些效应与 PPARGC1A（一种转录因子）的诱导有关。 在代谢、线粒体重塑和线粒体调节中具有重要作用的共激活剂 生物发生。这种效应伴随着细胞凋亡的减少和线粒体形态的正常化 肺泡 II 型细胞中的功能，依赖于完整的有丝分裂发生和线粒体自噬途径。最后， 在从大量、特征明确的 IPF 患者纵向队列中获得的血浆样本中，我们 确定了循环线粒体 DNA 水平的增加，这与显着增加相关 这些患者的死亡率。考虑到甲状腺激素对于损伤后的修复至关重要 激活促生存和抗氧化信号通路以及调节线粒体稳态和 代谢，甲状腺功能减退症与多种慢性疾病的不良预后相关 包括 IPF，我们假设通过增强甲状腺激素恢复线粒体稳态 信号传导可以为上皮保护和解决肺结核建立可行的治疗策略 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 信号传导通过诱导有丝分裂发生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引起线粒体生物学变化，导致器官纤维化减少。目标 3： 为了确定 Sobetirome 的潜在用途，Sobetirome 是一种相对缺乏甲状腺、心脏和甲状腺功能的拟甲状腺药物。 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 使用增强甲状腺激素信号传导作为人类抗纤维化策略。

项目成果

Integrative analyses for the identification of idiopathic pulmonary fibrosis-associated genes and shared loci with other diseases.

识别特发性肺纤维化相关基因和与其他疾病共享位点的综合分析。

• 发表时间: 2023-08
• 影响因子: 10
• 作者: Chen, Ming;Zhang, Yiliang;Adams, Taylor;Ji, Dingjue;Jiang, Wei;Wain, Louise V;Cho, Michael;Kaminski, Naftali;Zhao, Hongyu
• 通讯作者: Zhao, Hongyu

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。

• 发表时间: 2023-10-01
• 影响因子: 24.7
• 作者: Schupp, Jonas C;Manning, Edward P;Chioccioli, Maurizio;Kamp, Jan C;Christian, Leonard;Ryu, Changwan;Herzog, Erica;Kühnel, Mark P;Prasse, Antje;Kaminski, Naftali;Jonigk, Danny D;Homer, Robert J;Yale
• 通讯作者: Yale

Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

特发性肺纤维化易感性的全基因组 SNP-性别相互作用分析。

• 发表时间: 2024-01-15
• 作者: Leavy, Olivia C;Goemans, Anne F;Stockwell, Amy D;Allen, Richard J;Guillen;Hernandez;Adegunsoye, Ayodeji;Booth, Helen L;CleanUP;Cullinan, Paul;Fahy, William A;F
• 通讯作者: F

From COVID to fibrosis: lessons from single-cell analyses of the human lung.

从新冠病毒到纤维化：人肺单细胞分析的教训。

• 发表时间: 2022-06-13
• 影响因子: 4.5
• 作者: Justet, Aurelien;Zhao, Amy Y;Kaminski, Naftali
• 通讯作者: Kaminski, Naftali

Single-cell connectomic analysis of adult mammalian lungs.

成年哺乳动物肺部的单细胞连接组分析。

• 发表时间: 2019
• 影响因子: 13.6
• 作者: Raredon, Micha Sam Brickman;Adams, Taylor Sterling;Suhail, Yasir;Schupp, Jonas Christian;Poli, Sergio;Neumark, Nir;Leiby, Katherine L;Greaney, Allison Marie;Yuan, Yifan;Horien, Corey;Linderman, George;Engler, Alexander J;Boffa, Daniel J;Kluge
• 通讯作者: Kluge