(U Chicago Core A) ? The cerebral cavernous malformation (CCM) is a common hemorrhagic vascular anomaly, presenting in sporadic and familial autosomal dominant forms, with three known gene loci. It affects more than a million Americans, predisposing them to a lifetime risk of stroke and epilepsy. There is currently no therapy to prevent the genesis or clinical progression of CCM lesions. Previous research by the four lead investigators in this Program Project has identified somatic mutations and aberrant molecular signaling associated with the silencing of CCM genes, postulated to be relevant to disease pathogenesis. Yet critical knowledge gaps remain about the role of somatic mutations and the primacy of RhoA Kinase dependent and independent signaling in the actual genesis of CCM lesions. Researchers have employed to date different models of lesion genesis, and varying standards and approaches to assessing vascular phenotype. This has limited the comparability of results from different studies. The four groups assembled herein are uniquely positioned to help answer these questions, through specific hypotheses in respective projects, the sharing of models and biomarkers optimized at the respective sites, and leveraging their collective expertise and proven collaborations. Each of the proposed projects will be enhanced by and take advantage of a Phenotyping and Human Tissue Core Unit at the University of Chicago, with shared infrastructure and unparalleled expertise in characterizing various signatures of the CCM phenotype, enhancing the synergy and throughput of the respective projects.
Three Specific Aims motivating this core unit include (1) mouse CCM phenotype, (2) human CCM lesion phenotype, and (3) laser microdissection, genomics and bioinformatics. The Core will help increase the experimental throughput at the three project sites by allowing them to ?outsource? the highly labor intensive facet of phenotype analysis. It will facilitate the sharing and use of human tissue in the various experiments. It will optimize and standardize the assessment of murine and human lesions, immunohistochemistry conditions and the laser capture microdissection of relevant lesions and cells, for genomic and differential transcriptome studies. The core will streamline the morphometric analysis of lesion burden and phenotypic signatures, apply uniform models of statistical analyses, and allow blinded and objective comparisons of these features with various signaling manipulations across projects, institutions and models. It will facilitate the probing of biomarkers generated at one site in tissues generated at other sites, and the tracking of multiple biomarkers from different sites in the same human lesion specimens. It will streamline bioinformatics analysis of cDNA libraries from murine and human lesion endothelial cells for use by the three project sites. In a strategic sense, the consolidation of this infrastructure will help the teams transition into future high throughput preclinical testing of the safety, effectiveness and dose optimization of specific drugs and combination therapies targeting signaling aberrations which emerge from this Program Project.
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