Telomerase Mutations and the Pulmonary Fibrosis–Bone Marrow Failure Syndrome Complex

doi:10.1056/nejmc1206730

Cited by 24 publications

(8 citation statements)

References 5 publications

(6 reference statements)

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“…It may also appear remarkable that fetal-stage lung organoids can model an age-associated disease to at least some extent. The additional stress of tissue culture may promote the early appearance of disease features—in particular, features of a disease such as IPF, in which both age and telomeropathy are prime risk factors (Alder et al, 2008, 2011, 2015a; Armanios et al, 2007, 2012a, 2012b; Ryu et al, 2014). Tissue culture-induced senescence and stress may therefore cause the premature appearance of fibrosis in organoids with mutations that predispose to fibrosis in patients.…”

Section: Discussionmentioning

confidence: 99%

“…The nature of some mutations associated with IPF, such as those in the genes encoding surfactant proteins (SFTPs) A2 (Wang et al, 2009) and SFTPC (Lawson et al, 2004; Nogee et al, 2001; Nureki et al, 2018; Thomas et al, 2002), suggests that injury to type II alveolar epithelial (ATII) cells, the surfactant-producing cells of the alveoli, is critical to pathogenesis (Fingerlin et al, 2013; Seibold et al, 2011; Yang et al, 2015; Zhang et al, 2011). Eight percent to 15% of patients with familial IPF have heterozygous mutations in the reverse transcriptase (hTERT) or RNA component (hTERC) of telomerase (Alder et al, 2008, 2011, 2015a; Armanios, 2012a, 2012b, 2007). Furthermore, several susceptibility loci have been identified through exome sequencing that affect telomere length (Stuart et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

et al. 2019

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SUMMARY The pathogenesis of idiopathic pulmonary fibrosis (IPF), an intractable interstitial lung disease, is unclear. Recessive mutations in some genes implicated in Hermansky-Pudlak syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity that is similar to IPF. We previously reported that HPS1−/−embryonic stem cell-derived 3D lung organoids showed fibrotic changes. Here, we show that the introduction of all HPS mutations associated with HPSIP promotes fibrotic changes in lung organoids, while the deletion of HPS8, which is not associated with HPSIP, does not. Genome-wide expression analysis revealed the upregulation of interleukin-11 (IL-11) in epithelial cells from HPS mutant fibrotic organoids. IL-11 was detected predominantly in type 2 alveolar epithelial cells in end-stage IPF, but was expressed more broadly in HPSIP. Finally, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in HPS4−/− organoids, suggesting IL-11 as a therapeutic target. hPSC-derived 3D lung organoids are, therefore, a valuable resource to model fibrotic lung disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

et al. 2019

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“…The physiological relevance of RAGE in the nucleus is hitherto unknown. Similar to ATM deficient murine models of ataxia telangiectasia ( 30 , 31 ) or persistent DSB signaling models ( 32 – 35 ), loss of RAGE affects pulmonary repair mechanisms resulting in pulmonary fibrosis ( 29 , 36 , 37 ) and other defective DNA DSB repair associated anomalies. Thus, the study of the physiological role of RAGE in the nucleus might help to understand not only steps critical for DNA repair, but also to unravel the connection between DNA repair, senescence and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Homeostatic nuclear RAGE–ATM interaction is essential for efficient DNA repair

Kumar

Fleming

Terjung

et al. 2017

Nucleic Acids Research

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The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE−/−), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis.

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“…of surfactant protein [ 50 ]), polymorphism (e.g. of IL-10 [ 51 ], IL-4 [ 52 ], Muc5B [ 53 ]), and telomerase mutations [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

A Mathematical Model of Idiopathic Pulmonary Fibrosis

2015

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Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology, and life expectancy of 3-5 years after diagnosis. The incidence rate in the United States is estimated as high as 15 per 100,000 persons per year. The disease is characterized by repeated injury to the alveolar epithelium, resulting in inflammation and deregulated repair, leading to scarring of the lung tissue, resulting in progressive dyspnea and hypoxemia. The disease has no cure, although new drugs are in clinical trials and two agents have been approved for use by the FDA. In the present paper we develop a mathematical model based on the interactions among cells and proteins that are involved in the progression of the disease. The model simulations are shown to be in agreement with available lung tissue data of human patients. The model can be used to explore the efficacy of potential drugs.

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Telomerase Mutations and the Pulmonary Fibrosis–Bone Marrow Failure Syndrome Complex

Cited by 24 publications

References 5 publications

Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

Homeostatic nuclear RAGE–ATM interaction is essential for efficient DNA repair

A Mathematical Model of Idiopathic Pulmonary Fibrosis

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