JCI insight最新文献_第3页

YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.178535

Wang Yang, Ming Zhang, Tian-Xing Zhang, Jia-Hui Liu, Man-Wei Hao, Xu Yan, Haicheng Gao, Qun-Ying Lei, Jiuwei Cui, Xin Zhou

{"title":"YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.","authors":"Wang Yang, Ming Zhang, Tian-Xing Zhang, Jia-Hui Liu, Man-Wei Hao, Xu Yan, Haicheng Gao, Qun-Ying Lei, Jiuwei Cui, Xin Zhou","doi":"10.1172/jci.insight.178535","DOIUrl":"https://doi.org/10.1172/jci.insight.178535","url":null,"abstract":"KRAS mutations are frequent in various human cancers. The development of selective inhibitors targeting KRAS mutations has opened a new era for targeted therapy. However, intrinsic and acquired resistance to these inhibitors remains a major challenge. Here, we found that cancer cells resistant to KRAS G12C inhibitors also display cross-resistance to other targeted therapies, such as inhibitors of RTKs or SHP2. Transcriptomic analyses revealed that the Hippo-YAP/TAZ pathway is activated in intrinsically resistant and acquired-resistance cells. Constitutive activation of YAP/TAZ conferred resistance to KRAS G12C inhibitors, while knockdown of YAP/TAZ or TEADs sensitized resistant cells to these inhibitors. This scenario was also observed in KRAS G12D-mutant cancer cells. Mechanistically, YAP/TAZ protects cells from KRAS inhibitor-induced apoptosis by downregulating the expression of proapoptotic genes such as BMF, BCL2L11, and PUMA, and YAP/TAZ reverses KRAS inhibitor-induced proliferation retardation by activating the SLC7A5/mTORC1 axis. We further demonstrated that dasatinib and MYF-03-176 notably enhance the efficacy of KRAS inhibitors by reducing SRC kinase activity and TEAD activity. Overall, targeting the Hippo-YAP/TAZ pathway has the potential to overcome resistance to KRAS inhibitors.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptomic profiling of thyroid eye disease orbital fat demonstrates differences in adipogenicity and IGF-1R pathway.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-20 DOI: 10.1172/jci.insight.182352

Dong Won Kim, Soohyun Kim, Jeong Han, Karan Belday, Emily Li, Nicholas Mahoney, Seth Blackshaw, Fatemeh Rajaii

{"title":"Transcriptomic profiling of thyroid eye disease orbital fat demonstrates differences in adipogenicity and IGF-1R pathway.","authors":"Dong Won Kim, Soohyun Kim, Jeong Han, Karan Belday, Emily Li, Nicholas Mahoney, Seth Blackshaw, Fatemeh Rajaii","doi":"10.1172/jci.insight.182352","DOIUrl":"https://doi.org/10.1172/jci.insight.182352","url":null,"abstract":"Despite recent advances in the treatment of thyroid eye disease thyroid-related eye disease (TED), marked gaps remain in our understanding of the underlying molecular mechanisms, particularly concerning the insulin-like growth factor-1 receptor (IGF-1R) pathway. To dissect the pathophysiology of TED, we used single-nucleus RNA-Seq to analyze orbital fat specimens from both patients with TED and matched individuals acting as controls. The analysis demonstrated a marked increase in the proportion of fibroblasts transitioning to adipogenesis in the orbital fat of patients with TED compared with that in control patients. This was associated with diverse alterations in immune cell composition. Significant alterations in the IGF-1R signaling pathway were noted between TED specimens and those from control patients, indicating a potential pathological mechanism driven by IGF-1R signaling abnormalities. Additionally, our data showed that linsitinib, a small-molecule inhibitor of IGF-1R, effectively reduced adipogenesis in TED orbital fibroblasts in vitro, suggesting its potential utility as a therapeutic agent. Our findings reveal that, beyond immune dysfunction, abnormal IGF-1R signaling leading to enhanced adipogenesis is a crucial pathogenic mechanism in TED.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 24","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-19 DOI: 10.1172/jci.insight.184451

Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

{"title":"Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4-related amyloidosis.","authors":"Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka","doi":"10.1172/jci.insight.184451","DOIUrl":"https://doi.org/10.1172/jci.insight.184451","url":null,"abstract":"With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy-lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly CKD patients remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied with mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance reflected by the accumulation of mitochondria-lysosome-related organelles, which depends on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn's disease.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-19 DOI: 10.1172/jci.insight.181481

Elena Layunta, Sofia Jäverfelt, Fleur C van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara Im Thulin, Bruce A Vallance, Thaher Pelaseyed

{"title":"MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn's disease.","authors":"Elena Layunta, Sofia Jäverfelt, Fleur C van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara Im Thulin, Bruce A Vallance, Thaher Pelaseyed","doi":"10.1172/jci.insight.181481","DOIUrl":"https://doi.org/10.1172/jci.insight.181481","url":null,"abstract":"Crohn's disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In non-inflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extra-intestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in CD patients. Our findings highlight MUC17 as an essential regiospecific line of defense in the small intestine with relevance for early epithelial defects in CD.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-19 DOI: 10.1172/jci.insight.183483

Joanna Y Wang, Sylvia N Michki, Sneha Sitaraman, Brandon J Banaschewski, Reshma Jamal, Jason J Gokey, Susan M Lin, Jeremy B Katzen, Maria C Basil, Edward Cantu, Jonathan A Kropski, Jarod A Zepp, David B Frank, Lisa R Young

{"title":"Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome.","authors":"Joanna Y Wang, Sylvia N Michki, Sneha Sitaraman, Brandon J Banaschewski, Reshma Jamal, Jason J Gokey, Susan M Lin, Jeremy B Katzen, Maria C Basil, Edward Cantu, Jonathan A Kropski, Jarod A Zepp, David B Frank, Lisa R Young","doi":"10.1172/jci.insight.183483","DOIUrl":"https://doi.org/10.1172/jci.insight.183483","url":null,"abstract":"Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and organoid modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8+ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Angiotensin receptor blockers modulate the lupus CD4+ T cell epigenome characterized by TNF family-linked signaling. 血管紧张素受体阻滞剂可调节以 TNF 家族相关信号为特征的狼疮 CD4+ T 细胞表观基因组。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-17 DOI: 10.1172/jci.insight.176811

Andrew P Hart, Jonathan J Kotzin, Steffan W Schulz, Jonathan S Dunham, Alison L Keenan, Joshua F Baker, Andrew D Wells, Daniel P Beiting, Terri M Laufer

{"title":"Angiotensin receptor blockers modulate the lupus CD4+ T cell epigenome characterized by TNF family-linked signaling.","authors":"Andrew P Hart, Jonathan J Kotzin, Steffan W Schulz, Jonathan S Dunham, Alison L Keenan, Joshua F Baker, Andrew D Wells, Daniel P Beiting, Terri M Laufer","doi":"10.1172/jci.insight.176811","DOIUrl":"10.1172/jci.insight.176811","url":null,"abstract":"In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from lupus patients and healthy individuals. Most lupus patients, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single cell approaches revealed that chromatin changes extended to naive CD4+ T cells; uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNFɑ, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs) which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling. PTH1R 和 IGF1 通过刺猬通路负反馈介导颅面骨重塑。

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-17 DOI: 10.1172/jci.insight.183684

Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J Rosen, Chenchen Zhou

{"title":"Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling.","authors":"Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J Rosen, Chenchen Zhou","doi":"10.1172/jci.insight.183684","DOIUrl":"https://doi.org/10.1172/jci.insight.183684","url":null,"abstract":"Regeneration of orofacial bone defects caused by inflammatory-related diseases or trauma remains an unmet challenge. Parathyroid hormone 1 receptor (PTH1R) signaling is a key mediator of bone remodeling whereas the regulatory mechanisms of PTH1R signaling in oral bone under homeostatic or inflammatory conditions have not been demonstrated by direct genetic evidence. Here we observed that deletion of PTH1R in Gli1+-progenitors led to increased osteogenesis and osteoclastogenesis. Single-cell and bulk RNA-seq analysis revealed that PTH1R suppresses the osteogenic potential of Gli1+-progenitors during inflammation. Moreover, we identified upregulated IGF1 expression upon PTH1R deletion. Dual deletion of IGF1 and PTH1R ameliorated the bone remodeling phenotypes in PTH1R-defienct mice. Furthermore, in vivo evidence revealed an inverse relationship between PTH1R and Hedgehog signaling, which was responsible for the upregulated IGF1 production. Our work underscored the negative feedback between PTH1R and IGF1 in craniofacial bone turnover, and revealed mechanisms modulating orofacial bone remodeling.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Orthotopic gastric cancer mouse model identifies trajectory of lymphatic metastasis.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-17 DOI: 10.1172/jci.insight.186565

Huafeng Fu, Qinbo Cai, Zhijun Zhou, Yulong He, Min Li, DongJie Yang

引用次数: 0

Airway-resident memory CD4 T-cell activation accelerates antigen presentation and T-cell priming in draining lymph nodes.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-17 DOI: 10.1172/jci.insight.182615

Caroline M Finn, Kunal Dhume, Eugene Baffoe, Lauren A Kimball, Tara M Strutt, K Kai McKinstry

{"title":"Airway-resident memory CD4 T-cell activation accelerates antigen presentation and T-cell priming in draining lymph nodes.","authors":"Caroline M Finn, Kunal Dhume, Eugene Baffoe, Lauren A Kimball, Tara M Strutt, K Kai McKinstry","doi":"10.1172/jci.insight.182615","DOIUrl":"https://doi.org/10.1172/jci.insight.182615","url":null,"abstract":"Specialized memory CD4 T cells that reside long-term within tissues are critical components of immunity at portals of pathogen entry. In the lung, such tissue-resident memory (TRM) cells are activated rapidly after infection and promote local inflammation to control pathogen levels before circulating T cells can respond. However, optimal clearance of Influenza A virus can require TRM and responses by other virus-specific T cells that reach the lung only several days after their activation in secondary lymphoid organs. Whether local CD4 TRM sentinel activity can impact the efficiency of T cell activation in secondary lymphoid organs is not clear. Here, we found that recognition of antigen by influenza -primed TRM in the airways promotes more rapid migration of highly activated antigen-bearing dendritic cells to the draining lymph nodes. This in turn accelerated the priming of naive T cells recognizing the same antigen, resulting in newly activated effector T cells reaching the lungs earlier than in mice not harboring TRM. Our findings thus reveal a circuit linking local and regional immunity whereby antigen recognition by TRM improves effector T cell recruitment to the site of infection though enhancing the efficiency of antigen presentation in the draining lymph node.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.

IF 6.3 1区医学

JCI insight Pub Date : 2024-12-10 DOI: 10.1172/jci.insight.181783

Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R Matthews, Peu Santra, Elliott H Sherr, Dylan K Chan

{"title":"Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.","authors":"Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R Matthews, Peu Santra, Elliott H Sherr, Dylan K Chan","doi":"10.1172/jci.insight.181783","DOIUrl":"https://doi.org/10.1172/jci.insight.181783","url":null,"abstract":"Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways have been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GCaMP is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db SPL) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure and was noise dose-dependent, with the pro-apoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae, but re-activated upon noise exposure. 106 dB noise exposure was associated with more persistent and expansive intercellular Ca2+ signaling wave activity. These findings demonstrated a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0