scholarly journals RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations

Stroke ◽  
2017 ◽  
Vol 48 (1) ◽  
pp. 187-194 ◽  
Author(s):  
Robert Shenkar ◽  
Changbin Shi ◽  
Cecilia Austin ◽  
Thomas Moore ◽  
Rhonda Lightle ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Murine Models ◽  
Kinase Inhibition ◽  
Cavernous Malformations ◽  
Rhoa Kinase

scholarly journals B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models

2016 ◽  
Vol 11 (2) ◽  
pp. 369-377 ◽  
Author(s):  
Changbin Shi ◽  
Robert Shenkar ◽  
Hussein A. Zeineddine ◽  
Romuald Girard ◽  
Maged D. Fam ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Depletion ◽  
Cerebral Cavernous Malformations ◽  
B Cell Depletion ◽  
Murine Models ◽  
Cavernous Malformations

Abstract 126: Phenotypic Features of Murine Models of Cerebral Cavernous Malformations

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hussein Zeineddine ◽  
Romuald Girard ◽  
Thomas Moore ◽  
Rhonda Lightle ◽  
Ying Cao ◽  
...  
Keyword(s):  
T Cells ◽  
Iron Deposition ◽  
Cerebral Cavernous Malformations ◽  
Murine Models ◽  
Lesion Area ◽  
Cavernous Malformations ◽  
Chronic Model ◽  
Chronic Models ◽  
Phenotypic Features ◽  
Rock Activity

Introduction: Cerebral cavernous malformations (CCM) are hemorrhagic lesions causing stroke and epilepsy. They develop with loss of function of three known genes in endothelial cells (ECs). Mice heterozygous for Ccm 1, 2 or 3 genes develop CCMs stochastically during life (“chronic models”), especially when bred in a background predisposing to somatic mutations ( p53 or Msh2 loss) . CCM lesions can also be generated in the developing hindbrain and retinas by Cre-recombinase induced homozygous loss of Ccm 1, 2, or 3 genes in the immediate postnatal period (“acute models”). We hypothesized that the CCM lesions which develop in the various models reflect different phenotypic features of the human disease. Methods: Eight murine models of CCM were used in this study and defined as being chronic ( Ccm1 +/- Msh2 -/- , Ccm3 +/- and Ccm3 +/- Trp53 -/- ) or acute ( Pdgfb iCreERT2 Ccm1 fl/fl , Pdgfb iCreERT2 Ccm3 fl/fl and Cdh5 CreERT2 Ccm1 fl/fl ). Volumetric lesion burden was assessed using micro-CT after adjusting for total brain volume. Other phenotypic markers were assessed including the prevalence of ECs with Rho-associated protein kinase (ROCK) activity, and quantitation of B and T cells infiltration and non-heme iron deposition in the CCM lesions. Results: The acute neonatal models showed higher adjusted volume lesion burden than the paired chronic model (p=0.013). CCM EC ROCK activity was similar in the acute and chronic models. Background brain EC ROCK activity in chronic models was higher than that in acute model (p=0.012). CCM lesions in chronic models (16 lesions/13 mice) had higher integrated iron intensity per lesion area compared to the acute lesions (12 lesions/9 mice) (p=0.03). Chronic lesions had a higher number of B cells (p=0.005), more T cells (p=0.04) per lesion area, and more combined lymphocytes (p=0.002) per lesion area compared to the acute model. Conclusion: The acute model harbored a significantly higher lesion burden making them suitable for studying lesion genesis mechanisms. The chronic model however is more suited to study the role of inflammation and iron deposition in CCM, hallmark features of clinically relevant CCM lesions in man.

scholarly journals Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease

2016 ◽  
Vol 271 ◽  
pp. 14-24 ◽  
Author(s):  
Romuald Girard ◽  
Hussein A. Zeineddine ◽  
Courtney Orsbon ◽  
Huan Tan ◽  
Thomas Moore ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Brain Disease ◽  
Cerebral Cavernous Malformations ◽  
Murine Models ◽  
Micro Computed Tomography ◽  
Cavernous Malformations

scholarly journals Phenotypic characterization of murine models of cerebral cavernous malformations

2018 ◽  
Vol 99 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Hussein A. Zeineddine ◽  
Romuald Girard ◽  
Laleh Saadat ◽  
Le Shen ◽  
Rhonda Lightle ◽  
...  
Keyword(s):  
Phenotypic Characterization ◽  
Cerebral Cavernous Malformations ◽  
Murine Models ◽  
Cavernous Malformations

scholarly journals Novel Murine Models of Cerebral Cavernous Malformations

Angiogenesis ◽  
2020 ◽  
Vol 23 (4) ◽  
pp. 651-666
Author(s):  
Matthew R. Detter ◽  
Robert Shenkar ◽  
Christian R. Benavides ◽  
Catherine A. Neilson ◽  
Thomas Moore ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Murine Models ◽  
Cavernous Malformations

scholarly journals A Series of 14 Representative Presentations of Cerebral Cavernous Malformations

2021 ◽  
pp. 101298
Author(s):  
Ryan Hudnall ◽  
Eric X. Chen ◽  
Patrick J Opperman ◽  
Sean Kelly ◽  
Justin A. Cramer ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

Genotype-phenotype correlations in cerebral cavernous malformations patients

2006 ◽  
Vol 60 (5) ◽  
pp. 550-556 ◽  
Author(s):  
Christian Denier ◽  
Pierre Labauge ◽  
Françoise Bergametti ◽  
Florence Marchelli ◽  
Florence Riant ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

Abstract 159: Exceptional Aggressiveness of CCM3 Phenotype

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tania J Rebeiz ◽  
Abdul Ghani Mikati ◽  
Darlene Simkhin ◽  
Cornelia Lee ◽  
Amy Akers ◽  
...  
Keyword(s):  
Spontaneous Mutation ◽  
Mutation Screening ◽  
High Sensitivity ◽  
Skin Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cognitive Disability ◽  
Cavernous Malformations ◽  
Patient Advocacy Group ◽  
Sporadic Cases

Introduction: Familial forms of cerebral cavernous malformations (CCM) account for about 1/3 of cases, involving autosomal dominant inheritance at 1 of 3 gene loci. Few studies have examined any special features of the rarest cases with CCM3 (PDCD10 ) mutation at q3, constituting <15 % of probands genotyped by sequential mutation screening, and <2% of CCM cases at large. Hypothesis: We hypothesize that CCM3 cases have unique phenotypic features not recognized in the more common CCM1 and 2 families, or in sporadic cases. Methods: Twelve probands including 17 subjects with confirmed CCM3 mutations were prospectively enrolled through systematic facilitated referral by the patient advocacy group Angioma Alliance. Clinical features were catalogued, including high sensitivity susceptibility weighted imaging (SWI). Rates of overt hemorrhage were determined based on adjudicated criteria. Comparisons were made to systematic literature review of natural history data on non-CCM3 cases. Results: The first overt hemorrhage occurred most often in the 1st decade of life (mean age 5.8). Nine of 17 subjects (52%) suffered 30 overt hemorrhages, with an estimated incidence of 6.7 % /patient/year based on exposure risk since birth, and 17% /patient/year based on risk since first symptom onset. Lesion burden on SWI was exceptionally high, >100 lesions in 28%, and > 20 lesions in 72% of cases, respectively. Adjusted bleed rate was <0.5% /lesion/year. New SWI lesions formed at a rate of 2.7/patient/year in prospective follow-up, and 1.8/patient/year based on years since birth. Scoliosis was found in 47% (an association not recognized previously), skin lesions in 29.4%, and brain tumors in 29.4% of cases, respectively. Cognitive disability affected 47% of cases, mostly in association with high lesion burden. Six of 15 cases with parental screening (40%) represented a spontaneous mutation. Conclusion: CCM3 is exceptionally aggressive compared to other familial and sporadic CCM. High risks of bleeding and cognitive disability mostly reflect severe lesion burden early in life, rather than a higher risk per lesion. These results will inform the design of clinical trials, urgently needed to address this unique CCM cohort.

Sign in / Sign up

Export Citation Format

Share Document