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Phenotypic characterization of murine models of cerebral cavernous malformations.

Publication ,  Journal Article
Zeineddine, HA; Girard, R; Saadat, L; Shen, L; Lightle, R; Moore, T; Cao, Y; Hobson, N; Shenkar, R; Avner, K; Chaudager, K; Koskimäki, J ...
Published in: Lab Invest
March 2019

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.

Duke Scholars

Published In

Lab Invest

DOI

EISSN

1530-0307

Publication Date

March 2019

Volume

99

Issue

3

Start / End Page

319 / 330

Location

United States

Related Subject Headings

  • rho-Associated Kinases
  • T-Lymphocytes
  • Phenotype
  • Pathology
  • Occludin
  • Mutation
  • Microfilament Proteins
  • Mice, Transgenic
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
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MLA
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Zeineddine, H. A., Girard, R., Saadat, L., Shen, L., Lightle, R., Moore, T., … Awad, I. A. (2019). Phenotypic characterization of murine models of cerebral cavernous malformations. Lab Invest, 99(3), 319–330. https://doi.org/10.1038/s41374-018-0030-y
Zeineddine, Hussein A., Romuald Girard, Laleh Saadat, Le Shen, Rhonda Lightle, Thomas Moore, Ying Cao, et al. “Phenotypic characterization of murine models of cerebral cavernous malformations.Lab Invest 99, no. 3 (March 2019): 319–30. https://doi.org/10.1038/s41374-018-0030-y.
Zeineddine HA, Girard R, Saadat L, Shen L, Lightle R, Moore T, et al. Phenotypic characterization of murine models of cerebral cavernous malformations. Lab Invest. 2019 Mar;99(3):319–30.
Zeineddine, Hussein A., et al. “Phenotypic characterization of murine models of cerebral cavernous malformations.Lab Invest, vol. 99, no. 3, Mar. 2019, pp. 319–30. Pubmed, doi:10.1038/s41374-018-0030-y.
Zeineddine HA, Girard R, Saadat L, Shen L, Lightle R, Moore T, Cao Y, Hobson N, Shenkar R, Avner K, Chaudager K, Koskimäki J, Polster SP, Fam MD, Shi C, Lopez-Ramirez MA, Tang AT, Gallione C, Kahn ML, Ginsberg M, Marchuk DA, Awad IA. Phenotypic characterization of murine models of cerebral cavernous malformations. Lab Invest. 2019 Mar;99(3):319–330.

Published In

Lab Invest

DOI

EISSN

1530-0307

Publication Date

March 2019

Volume

99

Issue

3

Start / End Page

319 / 330

Location

United States

Related Subject Headings

  • rho-Associated Kinases
  • T-Lymphocytes
  • Phenotype
  • Pathology
  • Occludin
  • Mutation
  • Microfilament Proteins
  • Mice, Transgenic
  • Mice, Knockout
  • Mice