Brain Arteriovenous Malformation Genetics Study
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ABSTRACT:
PROVIDER: PRJNA648440 | ENA |
REPOSITORIES: ENA
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Project description:Brain Arteriovenous Malformation Genetics Study
| PRJNA648439 | ENA
Project description:Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous AV shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies. We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and ChIP-Seq analyses from isolated brain ECs. Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased EC density along AV shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired EC dynamics, we found increased Cdc42 activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase-mediated cellular functions in brain ECs. siRNA treated, RBPJ-deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including Apelin, which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. ChIP-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored EC morphology and AV connection diameter in Rbpj-mutant brain vessels. Conclusions: Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj mediated bAVM.
2023-02-01 | GSE223532 | GEO
Project description:Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous AV shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies. We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and ChIP-Seq analyses from isolated brain ECs. Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased EC density along AV shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired EC dynamics, we found increased Cdc42 activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase-mediated cellular functions in brain ECs. siRNA treated, RBPJ-deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including Apelin, which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. ChIP-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored EC morphology and AV connection diameter in Rbpj-mutant brain vessels. Conclusions: Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj mediated bAVM.
2023-02-01 | GSE223531 | GEO
Project description:European-American individuals of the GENOA cohort participating in the “Genetics of Microangiopathic Brain Injury” substudy, which investigates the genetic basis of alteration in brain structure detectable by magnetic resonance imaging. This analysis investigated the association of gene expression with age (at the time of cell transformation). Participants in this study are drawn from the GENOA study, a population-based study from Rochester, MN
2013-09-15 | E-GEOD-49531 | biostudies-arrayexpress
Project description:Object. Detailed and exact mechanisms underlying brain arteriovenous malformations (bAVM) are still confusing in clinic. Understanding the quantitative changes of proteins and signaling pathways would provide useful information for clinicians to understand the formation and development of bAVM and therefore give proper individual treatment strategies. This study was performed to establish a huge human bAVM proteome database by tandem mass tag (TMT)-labeling technique and detect the alteration of proteins and pathways in the development of human bAVM. Methods. This study used quantitative proteomics to profile protein changes with the 6-plex TMT labeling in bAVM lesions. Integrated bioinformatics analysis were used to classify and identify the altered proteins and relating signaling pathways. Western blot analyses were used to identify the reliability of the proteomic data. Results. Our work established one of the largest human bAVM proteome databases to date. A total of 1264 proteins were identified, among which the expression of 316 proteins were changed with 249 proteins upregulated. Bioinformatics analysis revealed a close relevance between cell-cell interactions including focal adhesion, tight junction, gap junction and the development of bAVM. Conclusions. Cell-cell interactions, including focal adhesion, tight junction and gap junction played vital roles in the formation and development of bAVM. Understanding the molecular mechanism underlying bAVM is important for the development of future therapeutic approaches, thereafter making precise and individual treatment strategies in clinic.
2017-01-20 | PXD003289 | Pride
Project description:European-American individuals of the GENOA cohort participating in the “Genetics of Microangiopathic Brain Injury” substudy, which investigates the genetic basis of alteration in brain structure detectable by magnetic resonance imaging. This analysis investigated the association of gene expression with age (at the time of cell transformation).
2013-09-15 | GSE49531 | GEO
Project description:Ischemic Stroke Genetics Study (ISGS)
| PRJNA75377 | ENA
Project description:VitGene Generalized Vitiligo Genetics Study
| PRJNA75597 | ENA
Project description:Brisbane Systems Genetics Study comprises of a total of 862 individuals from 374 families. Families consist of combinations of both MZ and DZ twin pairs, their siblings and for 72 families their parents.
2013-12-11 | GSE53195 | GEO
Project description:Genetics of Human Developmental Brain Disorders
| PRJNA160053 | ENA