The role of pericytes in the adult and the aging brain

周细胞在成人和衰老大脑中的作用

• 批准号: 8513440
• 负责人: Berislav V Zlokovic
• 金额: $ 33.62万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513440
• 关键词: Acute; Address; Adult; Affect; Age; Alleles; Animals; Astrocytes; Biology; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; CSPG4 gene; Cells; Cerebral Hypoxia; Cerebrum; Chronic; Confocal Microscopy; Core-Binding Factor; Data; Deposition; Development; Disease; Electrophysiology (science); Embryo; Endothelial Cells; Endothelium; Experimental Designs; Fibrin; Focal Adhesions; Genes; Goals; Health Care Costs; Hemoglobin; Hippocampus (Brain); Hypoxia; Immunoblot Analysis; Immunoglobulin G; Inflammatory Response; Inherited; Knowledge; Lasers; Learning; Length; Mediating; Membrane; Memory; Methods; Microcirculation; Microscopy; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotoxins; Pathogenesis; Pathologic; Pathway interactions; Performance; Perfusion; Pericytes; Permeability; Phenotype; Platelet-Derived Growth Factor Receptor; Play; Process; Proteins; Quantitative Autoradiography; Reporting; Research; Resolution; Role; Serum; Signal Pathway; Signal Transduction; Staining method; Stains; Stress; Structure; Techniques; Testing; Thrombin; Tight Junctions; Time; Tissues; Vertebral column; age related; aging brain; arm; base; behavior test; capillary; cerebral hypoperfusion; cerebrovascular; cytotoxic; density; design; hypoxyprobe-1; in vivo; insight; macromolecule; mathematical model; mutant; neglect; nervous system disorder; neuroinflammation; neuron loss; neurotoxic; neurovascular unit; new therapeutic target; novel therapeutic intervention; response

DESCRIPTION (provided by applicant): Pericytes are essential cells of the neurovascular unit. They are embedded within the vascular membrane of brain capillaries making direct focal contacts with the endothelium. The existence and role of pericytes has been neglected for a long time. Interactions between endothelial cells and pericytes are important for normal functions of the capillary vessel wall. In the embryonic CNS, pericytes play a key role in the development of the microcirculation. Still, the field is at the beginning of a journey to fully understand and appreciate the biology of brain pericytes and its implications for neurological disorders. The major goals of the proposed research are to determine how pericyte deficiency in the adult and the aging brain affects key neurovascular functions and neuronal structure and function. Our central hypothesis is that pericytes maintain critical neurovascular functions which are essential for normal brain performance. We hypothesize that pericyte loss in the adult brain leads to a progressive age-dependent vascular damage by two parallel pathways: (1) reductions in brain microcirculation causing diminished capillary perfusion, reduced local CBF and hypoxic tissue damage; and (2) BBB disruption leading to brain accumulation of several neurotoxic and vasculotoxic macromolecules. We next hypothesize that pericyte loss from the adult brain leads to microvascular degeneration and vascular-mediated secondary neurodegenerative changes followed by a general inflammatory response. To test our hypothesis we propose to use 3 models of cerebrovascular hypoplasia mediated by (1) an inherited embryonic loss of CNS pericytes and PDGFR¿ global deficiency (i.e., F7 mutants), (2) an inducible pericyte loss in the adult CNS with intact signaling pathways in pericytes (i.e., NG2-Cre;Pdgfr¿DTR mice) and (3) a primary cerebral endothelial hypoplasia in which pericytes remain intact (i.e., Meox2+/- mice) as a non-pericyte deficiency hypoplasia model with genetically intact PDGFR¿ signaling. Several state-of-the art techniques will be used including in vivo multiphoton microscopy, high resolution confocal microscopy, quantitative autoradiography, mathematical modeling of CBF and BBB permeability, methods to study neuronal structure and function (e.g., electrophysiology), behavioral tests and neuroinflammation. The proposed application will fill in the gap of our knowledge regarding the role of pericytes in the CNS and will likely have important implications for our understanding of a neurodegenerative process and treatment of it. We expect to generate definitive data showing that pericytes control key neurovascular functions necessary for normal structure and function of neurons and that loss of pericytes from the adult CNS has a key role in the development of microvascular and neuronal degeneration. This data should establish brain pericytes as a major new therapeutic target for neurodegenerative disorders.

描述（由适用提供）：周细胞是神经血管单元的必需细胞。它们被嵌入到与内皮直接局灶性接触的脑毛细管的血管膜中。周细胞的存在和作用长期以来一直被忽略。内皮细胞和周细胞之间的相互作用对于毛细血管壁的正常功能很重要。在胚胎中枢神经系统中，周细胞在微循环的发展中起关键作用。尽管如此，该领域仍在完全理解和欣赏脑周期的生物学及其对神经系统疾病的影响的过程中。拟议的研究的主要目标是确定成年人和衰老大脑的多发性缺乏症如何影响关键的神经血管功能以及神经元结构和功能。我们的中心假设是，时期保持关键的神经血管功能，这对于正常的大脑表现至关重要。我们假设成人大脑的周细胞丧失会导致两种平行途径逐渐依赖年龄的血管损伤：（1）脑微循环减少，导致毛细血管灌注减少，局部CBF减少和低氧组织损伤； （2）BBB破坏导致几种神经毒性和血管毒性大分子的大脑积累。接下来，我们假设成人大脑的周细胞丧失导致微血管变性和血管介导的次级神经退行性变化，然后进行一般的炎症反应。为了检验假设，我们建议使用3种模型，由（1）由（1）由（1）遗传的CNS周细胞和PDGFR？全球缺陷（即F7突变体），（2）成人CN诱导的per液中易于信号传播的pericyter Pathery in Pericypece和pericy preciate和ngg 2-cng 2-cn， （3）主要的大脑内皮性低质性下周细胞保持完整（即Meox2 +/-小鼠）作为一种非透明缺乏性下降性下降症模型，并具有一般完整的PDGFR信号传导。几种最先进的技术将用于体内多极子显微镜，高分辨率共焦显微镜，定量自显影术，CBF和BBB渗透性的数学模型，研究神经元结构和功能的方法（例如，电生理学），行为测试和神经膜片。拟议的应用将填补我们关于周细胞在中枢神经系统中的作用的知识空白，并且可能对我们对神经退行性过程和治疗的理解具有重要意义。我们期望生成确定的数据，表明周期控制着神经元正常结构和功能所必需的关键神经血管功能，而成人中枢神经系统的周期损失在微血管和神经元变性的发展中具有关键作用。该数据应确定大脑期为神经退行性疾病的主要新治疗靶点。