Identifying and Correcting Dementia-Associated Changes in the Blood-Brain Barrier

识别和纠正与痴呆相关的血脑屏障变化

• 批准号: 10031380
• 负责人: Lee L Rubin
• 金额: $ 236.6万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10031380
• 关键词: Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animal Model; Astrocytes; Bioinformatics; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Communication; Cell Surface Receptors; Cells; Cerebrovascular system; Cultured Cells; Data; Data Set; Defect; Dementia; Derivation procedure; Deterioration; Development; Disease; Endothelial Cells; Equilibrium; Evaluation; Functional disorder; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Transcription; Health; Health Care Costs; Hippocampus (Brain); Human; In Vitro; Individual; Knowledge; Ligands; Literature; Maintenance; Mediating; Modeling; Modification; Molecular; Mus; Natural regeneration; Neurodegenerative Disorders; Neurons; Nutrient; Oxidative Stress; Pathogenicity; Pathway interactions; Pericytes; Peripheral; Pharmacology; Phenotype; Play; Process; Property; Protocols documentation; Publishing; Recombinant Proteins; Rejuvenation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Stress; System; Testing; Time; TimeLine; Vascular Diseases; Vascular Smooth Muscle; Work; age related; aged; base; biological adaptation to stress; brain cell; brain endothelial cell; brain parenchyma; cell type; dementia risk; disease phenotype; experimental study; extracellular; human model; human pluripotent stem cell; improved; in vitro Model; in vivo; induced pluripotent stem cell; intercellular communication; mouse model; nerve stem cell; neutralizing antibody; novel; novel therapeutic intervention; novel therapeutics; single cell sequencing; single-cell RNA sequencing; stem cell model; transcriptomics

Late onset neurodegenerative diseases, such as Alzheimer’s disease (AD), affect more than 7 million Americans, with the associated healthcare costs currently reaching hundreds of billions of dollars per year (and constantly rising). It is known that the pathology of AD involves many more cell types than the neurons of the hippocampus and cortex. The cells that comprise the brain vasculature, including the endothelial cells, pericytes, astrocytes and smooth muscle cells are critically important in maintaining the balance of health and disease in the brain. In particular, many properties of the endothelial cells, including their roles in establishing the blood-brain barrier (BBB), delivering nutrients to the brain, and regulating the proliferation of neural stem cells, are essential to proper brain function. Studies from our lab and others have demonstrated that brain vasculature can be restored even after it has been damaged, suggesting new strategies for treating neurodegenerative disorders via improving the integrity of brain vasculature. In experiments detailed in this application, we propose to both identify and correct processes within the cells of the brain vasculature that are known to be affected in Alzheimer’s disease and other dementias. Some of our work is based on the acknowledgement that aging is the major risk factor for dementia and is also characterized by declining vasculature. As a step toward obtaining a comprehensive understanding of aging-associated changes in the brain, our lab recently published a large single-cell RNAseq study comparing young and old mouse brains. Here, we propose to exploit our knowledge of the gene expression changes that define the aging process to identify cellular and molecular factors critical to brain blood vessel function and the maintenance of the BBB in a mouse model of AD. First, we will test several different hypotheses concerning the cellular and molecular bases for the vascular defects in the AD brain. Surprisingly, recent literature suggests that some of these changes are mediated by soluble factors and may be reversible. To explore this possibility in greater detail, we will use our knowledge of the CNS network of cell-cell interactions mediated by secreted factors to identify potentially correctable changes that occur in AD vasculature. Finally, we will use our lab’s expertise in human induced pluripotent stem cells (iPSCs) to employ an in vitro model of the BBB. This in vitro platform will serve as an important complementary approach to the in vivo mechanistic evaluation of putative aging or rejuvenation factors in human brain vascular cells. At the same time, we propose modifications of the current in vitro system that should improve its ability to recapitulate properties of the in vivo BBB. Together, our proposed studies seek to identify and validate new modulators of brain vasculature and to elucidate how the functions of these modulators play a role in the maintenance or degradation of the BBB in dementia.

晚期发作神经退行性疾病，例如阿尔茨海默氏病（AD），会影响超过700万 美国人，相关的医疗保健费用目前每年达到数亿美元（和 不断上升）。众所周知，与AD的病理相比，AD的病理涉及更多细胞类型 海马和皮层。包括内皮细胞在内的脑脉管系统的细胞 周细胞，星形胶质细胞和平滑肌细胞对于维持健康的平衡至关重要 大脑中的疾病。特别是，内皮细胞的许多特性，包括它们在建立 血脑屏障（BBB），向大脑运送营养并控制神经茎的扩散 细胞对于适当的大脑功能至关重要。我们实验室和其他人的研究表明大脑 脉管系统即使在损坏后也可以恢复，提出了治疗的新策略 神经退行性疾病通过改善脑脉管系统的完整性。在此详细介绍的实验中 应用，我们建议识别和纠正大脑脉管系统中的细胞内的过程和纠正过程 已知在阿尔茨海默氏病和其他痴呆症中受到影响。我们的一些工作是基于 承认衰老是痴呆症的主要危险因素，也以下降为特征 脉管系统。作为对衰老相关变化的全面理解的一步 Brain，我们的实验室最近发表了一项大型的单细胞RNASEQ研究，比较了年轻小鼠的大脑。 在这里，我们建议探索我们对基因表达变化的了解，以将衰老过程定义为 识别对脑血管功能至关重要的细胞和分子因素以及BBB的维持 AD的鼠标模型。首先，我们将测试有关细胞和分子的几种不同的假设 广告大脑中血管缺陷的碱基。令人惊讶的是，最近的文献表明其中一些 变化是由固体因素介导的，可能是可逆的。为了更详细地探索这种可能性，我们 将利用我们对由分泌因素介导的细胞 - 细胞相互作用网络的了解来识别 Ad Vasculation发生的潜在可更改的变化。最后，我们将在人类中使用实验室的专业知识 诱导多能干细胞（IPSC）采用了BBB的体外模型。这个体外平台将服务 作为对假定衰老或体内机械评估的重要方法 人脑血管细胞中的恢复活力。同时，我们建议对电流的修改 体外系统应提高其概括体内BBB特性的能力。一起，我们提出了 研究旨在识别和验证脑脉管系统的新调节剂，并阐明 这些调节剂在痴呆症中BBB的维持或降解中发挥了作用。