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MTORC1 signaling in brain endothelial progenitors contributes to CCM pathogenesis in a Pdcd10-deficient mouse model

ABSTRACT: mTORC1 signaling in brain endothelial progenitors contributes to CCM pathogenesis in a Pdcd10-deficient mouse model

PROVIDER: PRJNA1033690 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26588022.fastq.gz	Fastqsanger.gz
	SRR26588023.fastq.gz	Fastqsanger.gz
	SRR26588024.fastq.gz	Fastqsanger.gz
	SRR26588025.fastq.gz	Fastqsanger.gz
	SRR26588026.fastq.gz	Fastqsanger.gz

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mTORC1 signaling in brain endothelial progenitors contributes to CCM pathogenesis in a Pdcd10-deficient mouse model

Project description:Cerebral vascular malformations (CCM) are primarily found within brain, where they result in increased risk for stroke, seizures and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier (BBB) formed by the brain neurovascular unit, and recent studies suggest that loss of CCM genes causes disruptions of BBB integrity as the inciting event for the development of CCM. CCM lesion is proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling in the subclass of brain EC/EPC for the CCM lesion initiation and progression are unclear. Here we employed single-cell RNA-sequencing (scRNA-seq) analyses in early stages of the brain EC-specific Ccm3 deletion (Pdcd10BECKO) microvessels and identified a unique EPC cluster with high stem cell markers but low BBB-associated genes. mTORC1, but not mTORC2, is activated in mouse and human CCM lesions and EPCs. Mechanistic studies suggest that CCM3 suppresses Cav1/caveolae-mediated cellular trafficking and complex formation of the mTORC1 signaling proteins. Genetic deficiency of Raptor (mTORC1), but not of Rictor (mTORC2), prevents CCM lesion formation in the Pdcd10BECKO model. Importantly, mTORC1 pharmacological inhibitor Rapamycin ameliorate the CCM pathogenesis in the Pdcd10BECKO mice, by suppressing lesion-forming EPC expansion while enhancing BBB maturation. Our data suggest that CCM3 is critical for maintaining BBB integrity, and CCM3 loss-induced mTORC1 signaling in brain EPCs initiate the CCM pathogenesis.

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Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Noninflammatory Hepatocellular Carcinoma

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Neuroinflammation and immunothrombosis transcriptional patterns in CCM lesions revealed by spatial transcriptomics

Project description:Cerebral cavernous malformation (CCM) immunothrombosis is the connection between immune cells, platelet activation, coagulation cascades and astrocyte-CCM endothelium interaction, and its excessive activation may contribute to neurological disabilities in CCM disease. We characterized the spatial organization of CCM immunothrombosis observed in Pdcd10BECKObrains under normoxic conditions using the murine 10X Genomics Visium Spatial Gene Expression platform.

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Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Noninflammatory Hepatocellular Carcinoma

Project description:mTORC1-driven noninflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC. Background & Aims: Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of noninflammatory HCC remains unclear. Methods: Spontaneous noninflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific Tsc1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results: We showed that LTsc1KO in mice triggered spontaneous noninflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated noncirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1 and fibroblast growth factor 21), and mTORC1–signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of noninflammatory HCC. Conclusion: Our findings reveal the mechanisms of mTORC1-driven noninflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC.

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Project description:The CCM endothelium is hypersensitive to angiogenesis and can induce a hypoxic program associated with changes in angiogenesis, inflammation, and endothelial-cell metabolism under normoxic conditions. However, the role of active drivers of angiogenesis as CCM disease modifiers in human disease remains unclear. To assess whether CCM reactive astrocytes with neuroinflammatory capacity respond to hypoxia-induced CCM exacerbation, we employed the astrocyte-specific (Aldh1l1-EGFP/Rpl10a) Translational Ribosome Affinity Purification (TRAP) system in combination with a CCM mouse model (Pdcd10BECKO;Aldh1l1-EGFP/Rpl10a). TRAP protocol was performed using Slco1c1-iCreERT2;Pdcd10fl/fl;Aldh1l1-EGFP/Rpl10a mice to isolate ribosomes from astrocytes as previously described. Astrocyte-TRAP mRNAs were from cerebral tissue of mice age P50 exposed to hypoxia or normoxia conditions.

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Loss of FOXC1 contributes to the corneal epithelial fate switch and pathogenesis

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