Uterine signaling networks in the pathogenesis of pulmonary lymphangioleiomyomatosis (LAM)

肺淋巴管平滑肌瘤病 (LAM) 发病机制中的子宫信号网络

• 批准号: 10633293
• 负责人: YAN XU
• 金额: $ 75.29万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633293
• 关键词: Affect; Age; Apoptosis; Attenuated; B-Cell Acute Lymphoblastic Leukemia; Binding; Breast Cancer Cell; Candidate Disease Gene; Cell Death; Cell physiology; Cells; ChIP-seq; Chromatin; Data; Development; Diagnosis; Diagnostic tests; Disease; Ectopic Expression; Estrogens; FRAP1 gene; Female; Gene Expression Alteration; Genes; Genomics; Homeobox; Hormones; Immunofluorescence Microscopy; Immunohistochemistry; In Vitro; Interdisciplinary Study; Invaded; Knock-out; Lesion; Life; Lung; Lung Lymphangioleiomyomatosis; Lung Neoplasms; Lung diseases; Lymphangioleiomyomatosis; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Morphology; Mus; Neoplasm Metastasis; Neoplasms; Pathogenesis; Patients; Population; Pre-Clinical Model; Prevalence; Progesterone; Proliferating; Rattus; Remission Induction; Remission Induction Therapy; Research; Resolution; Respiratory Failure; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Sirolimus; Steroids; TSC1 gene; TSC2 gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Transactivation; Transfection; Uterine Fibroids; Uterus; Woman; Work; antagonist; clinical diagnostics; cofactor; comparative; curative treatments; design; diagnostic biomarker; diagnostic tool; epigenomics; experience; follow-up; gene network; gene regulatory network; genetic signature; in vivo; insight; loss of function mutation; lung lesion; migration; mouse model; new therapeutic target; non-invasive optical imaging; novel; novel diagnostics; novel strategies; novel therapeutics; pre-clinical; preservation; public health relevance; pulmonary function; reproductive; response; single-cell RNA sequencing; small hairpin RNA; symptomatic improvement; synthetic peptide; transcription factor; tumorigenesis

PROJECT SUMMARY Lymphangioleiomyomatosis (LAM), a lung neoplasm affecting reproductive age women, is caused by loss-of- function mutations in tuberous sclerosis 1 (TSC1) or TSC2 genes. Hyperactivation of the mechanistic target of rapamycin 1 leads to cystic lung remodeling and progressive respiratory failure. Sirolimus therapy stabilizes lung function and improves symptoms in LAM patients, but the long-term benefit and toxicity are unknown, and some patients do not respond to therapy. LAM cells are metastatic but the primary tissue of origin is unknown. Unknown mechanisms underlying lung-specific metastasis, primary pathogenesis and female prevalence of LAM are obstacles to the development of new curative therapies. Our preliminary data from LAM lung single cell RNA sequencing (scRNAseq) analysis identified a unique population of cells (LAMCORE) expressing uterine- specific homeobox (HOX) transcription factors (TFs) that are not detected in normal lung; TF profiling of LAM patient-derived cells identified activation of Pre-B-cell leukemia homeobox 1 (PBX1), a cofactor of HOXs; comparative analysis of LAM lung scRNAseq and breast cancer cell PBX1-ChIPseq revealed overly represented LAMCORE signature genes with positive PBX1 binding peaks. Collectively, this strongly suggests a uterine origin of LAM cells and a central role of HOX/PBX1 signaling in LAM pathogenesis. The objective of this proposal is to identify mechanisms by which HOXs-associated gene networks regulate LAM pathogenesis and progression. Our central hypothesis is that HOX/PBX1 orchestrates a cell-specific gene network downstream of female hormones that regulates the survival and lung metastasis of LAMCORE cells. Three specific aims are proposed to delineate the molecular mechanisms through which HOX/PBX1 gene network contributes to LAM lesion metastasis, formation and progression. Aim 1: Determine pulmonary LAM-specific genomic and epigenomic responses and mechanisms underlying HOX/PBX1-mediated LAM pathogenesis. Aim 2: Determine the functional impacts of HOX/PBX1 network genes on metastatic potentials of LAM-derived cells in vitro and in vivo. Aim 3: Determine the effect of the HOX/PBX1 antagonist, HXR9, singly or in combination with Sirolimus, on estrogen-promoted lung metastasis potentials and lung remodeling in vivo. The completion of this proposal will provide for the first time: 1) a high-resolution integrative genomic/epigenomic blueprint of the LAMCORE cells, 2) a LAMCORE cell-specific HOX/PBX1 gene network with predicted key regulatory factors and targets within the network for follow-up perturbation and clinical diagnostic tests, 3) novel mechanistic insights into HOX/PBX1 regulatory circuits and their functional impact on LAM pathogenesis, and 4) preclinical proof-of-principle evidence for targeting HOX/PBX1-regulated female hormone-mediated LAM progression as a novel remission-inducing therapeutic strategy for LAM patients. Our work has major biomedical relevance for understanding LAM pathogenesis, developing new approaches for LAM diagnosis and designing alternative remission-inducing therapeutic strategies to maximize the benefit/toxicity ratio LAM treatment.

项目总结

项目成果

Pretreatment of aged mice with retinoic acid supports alveolar regeneration via upregulation of reciprocal PDGFA signalling.

• DOI: 10.1136/thoraxjnl-2020-214986
• 发表时间: 2021-05
• 期刊: Thorax
• 影响因子: 10
• 作者: Gokey JJ;Snowball J;Green J;Waltamath M;Spinney JJ;Black KE;Hariri LP;Xu Y;Perl AK
• 通讯作者: Perl AK

Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.

• DOI: 10.1038/s41467-023-36810-8
• 发表时间: 2023-03-02
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Uehara, Yasuaki;Tanaka, Yusuke;Zhao, Shuyang;Nikolaidis, Nikolaos M.;Pitstick, Lori B.;Wu, Huixing;Yu, Jane J.;Zhang, Erik;Hasegawa, Yoshihiro;Noel, John G.;Gardner, Jason C.;Kopras, Elizabeth J.;Haffey, Wendy D.;Greis, Kenneth D.;Guo, Jinbang;Woods, Jason C.;Wikenheiser-Brokamp, Kathryn A.;Kyle, Jennifer E.;Ansong, Charles;Teitelbaum, Steven L.;Inoue, Yoshikazu;Altinisik, Goksel;Xu, Yan;McCormack, Francis X.
• 通讯作者: McCormack, Francis X.

Guided construction of single cell reference for human and mouse lung.

• DOI: 10.1038/s41467-023-40173-5
• 发表时间: 2023-07-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Guo, Minzhe;Morley, Michael P.;Jiang, Cheng;Wu, Yixin;Li, Guangyuan;Du, Yina;Zhao, Shuyang;Wagner, Andrew;Cakar, Adnan Cihan;Kouril, Michal A.;Jin, Kang;Gaddis, Nathan C.;Kitzmiller, Joseph A. M.;Stewart, Kathleen;Basil, Maria C.;Lin, Susan M. A.;Ying, Yun;Babu, Apoorva P.;Wikenheiser-Brokamp, Kathryn A.;Mun, Kyu Shik N.;Naren, Anjaparavanda P. S.;Clair, Geremy S.;Adkins, Joshua N. J.;Pryhuber, Gloria S. L.;Misra, Ravi S.;Aronow, Bruce J.;Tickle, Timothy L. E.;Salomonis, Nathan A.;Sun, Xin;Morrisey, Edward E.;Whitsett, Jeffrey A.;Xu, Yan
• 通讯作者: Xu, Yan

Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.

单细胞多组学鉴定肺泡毛细血管发育不良背后的细胞和遗传网络。

• DOI: 10.1164/rccm.202210-2015oc
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Guo,Minzhe;Wikenheiser-Brokamp,KathrynA;Kitzmiller,JosephA;Jiang,Cheng;Wang,Guolun;Wang,Allen;Preissl,Sebastian;Hou,Xiaomeng;Buchanan,Justin;Karolak,JustynaA;Miao,Yifei;Frank,DavidB;Zacharias,WilliamJ;Sun,Xin;Xu,Yan;Gu,
• 通讯作者: Gu,

Surfactant protein C mutation links postnatal type 2 cell dysfunction to adult disease.

• DOI: 10.1172/jci.insight.142501
• 发表时间: 2021-07-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Sitaraman S;Martin EP;Na CL;Zhao S;Green J;Deshmukh H;Perl AT;Bridges JP;Xu Y;Weaver TE
• 通讯作者: Weaver TE