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

脑血管的比较转录组：年龄、高血压和糖尿病

• 批准号: 7938610
• 负责人: Eng H. Lo
• 金额: $ 63.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938610
• 关键词: Affect; Age; Aging; Algorithms; Atlases; Bioinformatics; Biometry; Blood - brain barrier anatomy; Blood Vessels; Boston; Brain; Cell Separation; Central Nervous System Diseases; Cerebrum; Collaborations; Corpus Callosum; Data; Databases; Diabetes Mellitus; Disease; Freezing; Fresh Tissue; Frozen Sections; Functional disorder; Future; Gene Cluster; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Germany; Goals; Grant; Heart; Human; Hypertension; Institutes; International; Kidney; Knowledge; Messenger RNA; Molecular Profiling; Mus; Nerve Degeneration; Neurology; Neurons; Organ; Pathway interactions; Pattern; Pattern Recognition; Phenotype; Play; Research; Research Personnel; Resources; Role; Smooth Muscle Myocytes; Statistical Models; Stroke; Tight Junctions; Tissues; age effect; comparative; db/db mouse; diabetic; gene discovery; genome wide association study; gray matter; laser capture microdissection; mRNA Expression; member; mouse genome; new therapeutic target; normotensive; novel; professor; public health relevance; research study; stroke therapy; white matter

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.

描述（由申请人提供）：脑血管在卒中的病理生理学中起关键作用。我们都“知道”脑血管可能与其他器官的血管不同。例如，脑血管具有独特的紧密连接，有助于血脑屏障。但除了这种屏障表型，没有太多的其他是已知的。令人惊讶的是，从未对脑血管与其他器官的血管进行过系统的分析。在这个RC 2提案中，我们试图填补这一重要的知识空白。我们的总体目标是组装一个比较转录组（mRNA表达谱）的内皮细胞和平滑肌细胞在小鼠脑，心脏和肾脏。我们将提出以下问题：1。小鼠脑灰质与白色物质中血管基因表达是否存在差异？2.脑血管的基因表达谱与心脏和肾脏的基因表达谱不同吗？3.与心脏和肾脏相比，年龄、高血压和糖尿病对脑血管的影响是否不同？将以两种互补的方式收集内皮细胞和平滑肌细胞：新鲜冷冻组织的激光捕获显微切割和新鲜制备的全组织匀浆的原代细胞分离。基因表达将使用Affyoung Mouse Genome 430 2.0芯片进行分析。对于年龄，我们将比较“年轻”（5个月）与“年老”（15个月）C57 B16小鼠。对于高血压，我们将比较血压正常的BPN/3 J小鼠与自发性高血压BPH/2 J小鼠。对于糖尿病，我们将比较匹配的野生型对照与糖尿病db/db小鼠。该项目将产生一个新的数据库，可供所有中风研究人员用于研究新的假设，机制和目标。就血管功能障碍可能在神经退行性变中发挥作用而言，这些结果也可能影响广泛的其他中枢神经系统疾病。最后，虽然我们的主要重点是中风，但了解两种主要疾病（高血压和糖尿病）如何系统地影响血管基因表达，对许多其他生物医学领域也应该是广泛有用的。 公共卫生相关性：目前尚无临床有效的脑卒中神经保护治疗。最近的数据表明，仅仅关注神经元是不够的，大脑中的血管非常重要。然而，没有人知道这些脑血管与我们身体其他器官的血管有何不同。在这里，我们试图找出脑血管的完整基因表达谱，并将其与心脏和肾脏进行比较。我们还将发现衰老、高血压和糖尿病是如何改变这些基因模式的。这个数据库对于中风研究来说是无价的，在未来寻找新的治疗靶点。