Cerebral vascular malformations (CVMs) are prevalent in up to 4% of the population and are a common cause of stroke and epilepsy. Mechanisms predisposing to their genesis and progression have not been elucidated and their clinical course remains unpredictable. The candidate is a clinician- scholar in his 12th year post-residency training with focused interests in neurovascular surgery, having contributed seminal clinical-pathologic correlations and novel classification of CVMs. He has mentored students and residents in their first exposure to clinical research, resulting in numerous peer-reviewed publications by these trainees, several of whom are pursuing careers in academic neurosurgery. The proposed mid-career investigator award aims to expand and protect the candidate's committed time to patient-oriented research and mentoring of beginning clinician- investigators, within the framework of ongoing study on pathobiology of CVMs (R01NS36194) and other established collaborations. The candidate proposes to expand this work, hypothesizing that the emerging spectrum of CVM genotypes is associated with different clinical phenotypic manifestations of disease.
In Specific Aim 1, cases of inherited arteriovenous malformations are screened for mutations in recently identified HHT genes, and cases of inherited cavernous malformations for CCM genes; the spectrum of clinical manifestations (penetrance, radiological lesion appearance, non-neurologic manifestations, age at clinical presentation and risk of stroke and epilepsy) are compared among cases with different genotypes and with sporadic cases.
In Specific Aim 2, lesion histopathology, immunohistochemistry and ultrastructure are systematically compared among various categories of genotype; and in Specific Aim 3, cultured cell lines isolated from the different categories of excised CVM lesions are compared for differential expression of angiogenesis receptors and respective gene products. it is anticipated that this translational research will contribute toward a classification of CVMs based on biologic mechanisms and more rational strategies for screening, predicting, explaining and potentially modifying their clinical behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24NS002153-05
Application #
6639328
Study Section
NST-2 Subcommittee (NST)
Program Officer
Gwinn, Katrina
Project Start
2000-06-23
Project End
2003-11-30
Budget Start
2003-04-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$6,979
Indirect Cost
Name
University of Colorado Denver
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Dey, Mahua; Turner, Michael S; Pytel, Peter et al. (2011) A ""pseudo-cavernoma"" - an encapsulated hematoma of the choroid plexus. J Clin Neurosci 18:846-8
Shenkar, Robert; Venkatasubramanian, Palamadai N; Wyrwicz, Alice M et al. (2008) Advanced magnetic resonance imaging of cerebral cavernous malformations: part II. Imaging of lesions in murine models. Neurosurgery 63:790-7;discussion 797-8
Shenkar, Robert; Venkatasubramanian, Palamadai N; Zhao, Jin-cheng et al. (2008) Advanced magnetic resonance imaging of cerebral cavernous malformations: part I. High-field imaging of excised human lesions. Neurosurgery 63:782-9;discussion 789
Shenkar, Robert; Shi, Changbin; Check, Irene J et al. (2007) Concepts and hypotheses: inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations. Neurosurgery 61:693-702;discussion 702-3
Shi, Changbin; Shenkar, Robert; Batjer, H Hunt et al. (2007) Oligoclonal immune response in cerebral cavernous malformations. Laboratory investigation. J Neurosurg 107:1023-6
Gault, Judith; Sain, Stephan; Hu, Ling-Jia et al. (2006) Spectrum of genotype and clinical manifestations in cerebral cavernous malformations. Neurosurgery 59:1278-84; discussion 1284-5
Gault, Judith; Shenkar, Robert; Recksiek, Peter et al. (2005) Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 36:872-4
Shenkar, Robert; Sarin, Hemant; Awadallah, Nabil A et al. (2005) Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations. Neurosurgery 56:343-54
Shenkar, Robert; Elliott, J Paul; Diener, Katrina et al. (2003) Differential gene expression in human cerebrovascular malformations. Neurosurgery 52:465-77; discussion 477-8
Uranishi, Ryunosuke; Awadallah, Nabil A; Ogunshola, Omolara O et al. (2002) Further study of CD31 protein and messenger ribonucleic acid expression in human cerebral vascular malformations. Neurosurgery 50:110-5; discussion 115-6

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