Brain vascular malformations and blood-brain barrier defects represent important substrates for developing stroke, epilepsy and other neuropathological diseases. The most common type of brain malformation closely associated with stroke is the cerebral cavernous malformations (CCMs), which affect approximately 0.5% of population. Recognized as inherited and sporadic, CCMs are characterized as a single or multi- cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in the brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and an inflammatory response in brain parenchyma. Although significant progress has been made in defining the genes mutations involved in the inherited CCM3 form, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The proposed study is designed to elucidate critical molecular events involved in impairment of the brain endothelial barrier in CCM3 and CCm3 lesion progression. It will highlight the role of connexin 43 isoform (Cx43- 20kDa), one of the protein identify by our screening analysis to be highly expressed in condition of loss of CCM3 function in brain endothelial cells in driving the brain endothelial and barrier injury in CCM3. Specifically, it will be evaluated a) the role of Cx43-20kDa in generating gap junctions and hemi-channels in brain endothelial cells that will facilitate injury spread in CCM3-KD conditions and b) the benefits of blocking Cx43-20kDa and gap junction on CCM3 lesion progression. Collectively, these studies will provide new information related to the mechanisms of maintenance of brain endothelial barrier that is relevant also to multiple disease states and will, hopefully, elucidate novel therapeutic strategies to restore the vascular hyperpermeability.

Public Health Relevance

LAY DESCRIPTION Cerebral cavernous malformation type-3 is a vascular malformation characterized by thin-walled vascular cavities that may rupture. The purpose of this study is to highlight the molecular mechanisms underlying vessel hyperpermeability in this condition. This may provide a foundation for developing novel therapeutic strategies to lessen the impact of this disease as well as other neurological conditions that affect the blood-brain barrier.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS111205-01
Application #
9723874
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Koenig, James I
Project Start
2019-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109