Comparative transcriptome of brain blood vessels: age, hypertension and diabetes

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DESCRIPTION (Provided by Applicant): Cerebral blood vessels play a key role in the pathophysiology of stroke. We all "know" that brain blood vessels are likely to be different from vessels in other organs. For example, brain blood vessels have unique tight junctions that contribute to the blood-brain barrier. But beyond this barrier phenotype, not much else is known. Surprisingly, a systematic analysis of brain blood vessels comparing them with those from other organs has never been performed. In this RC2 proposal, we seek to fill this important gap in knowledge. Our overall goal is to assemble a comparative transcriptome (mRNA expression profiles) of endothelial and smooth muscle cells in mouse brain, heart and kidney. We will ask the following questions: 1. Are there differences in vascular gene expression in gray matter vs. white matter of mouse brain? 2. Are gene expression profiles of brain blood vessels different from those in heart and kidney? 3. Will age, hypertension and diabetes affect brain blood vessels differently compared to those in heart and kidney? Endothelial and smooth muscle cells will be collected in two complementary ways: laser capture microdissection of fresh-frozen tissue, and primary cell isolation from freshly prepared whole tissue homogenates. Gene expression will be analyzed with the Affymetrix Mouse Genome 430 2.0 chip. For age, we will compare "young" (5 month) vs. "old" (15 month) C57Bl6 mice. For hypertension, we will compare normotensive BPN/3J mice vs. spontaneously hypertensive BPH/2J mice. For diabetes, we will compare matching wildtype controls vs. diabetic db/db mice. This project should yield a novel database that can be used by all stroke researchers to investigate new hypotheses, mechanisms and targets. Insofar as vascular dysfunction may play a role in neurodegeneration, these results can also impact a wide spectrum of other CNS disorders. And finally, although our primary focus here is on stroke, gaining an understanding of how two major diseases (hypertension and diabetes) systematically affect vascular gene expression should be broadly useful for many other biomedical fields as well. PUBLIC HEALTH RELEVANCE: There is no clinically effective neuroprotective therapy for stroke. Recent data suggest that focusing on neurons alone is not enough, and that blood vessels within the brain are very important. Yet, no one knows how these brain blood vessels are different from blood vessels in other organs in our body. Here, we seek to find out the full gene expression profile of brain blood vessels, and compare it with heart and kidney. And we will also find out how aging, hypertension and diabetes alter these gene patterns. This database should be invaluable for stroke research, in terms of finding new therapeutic targets in the future.