The role of pericytes in the adult and the aging brain

描述(申请人提供)：周细胞是神经血管单位的基本细胞。它们嵌入在脑毛细血管的血管膜中，与内皮细胞直接局部接触。周细胞的存在和作用长期以来一直被忽视。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是重要的。在胚胎中枢神经系统中，周细胞在微循环发育中起着关键作用。尽管如此，该领域仍处于充分了解和欣赏脑周细胞的生物学及其对神经疾病的影响的旅程的开始。这项拟议研究的主要目标是确定成人和衰老大脑中的周细胞缺陷如何影响关键的神经血管功能和神经元结构和功能。我们的中心假设是，周细胞维持关键的神经血管功能，这对正常的大脑功能是必不可少的。我们假设，成人大脑中周细胞的丢失通过两条平行的途径导致进行性的年龄依赖性血管损伤：(1)脑微循环减少，导致毛细血管灌注量减少，局部CBF减少和缺氧组织损伤；(2)血脑屏障破坏导致脑内几种神经毒性和血管毒性大分子的积累。接下来，我们假设成人大脑中的周细胞丢失会导致微血管变性和血管介导的继发性神经退行性改变，随后是全身炎症反应。为了验证我们的假设，我们建议使用三种脑血管发育不良模型，该模型由(1)遗传性CNS周细胞胚胎丢失和PDGFR？全球缺陷(即，F7突变体)，(2)成人CNS周细胞可诱导性周细胞丢失，周细胞信号通路完整(即NG2-CRE；PDGFR？DTR小鼠)和(3)周细胞保持完整的原发脑内皮细胞发育不良(即，Meox2+/-小鼠)作为具有PDGFR？信号完整的非周细胞缺陷发育不良模型。将使用几种最先进的技术，包括体内多光子显微镜、高分辨率共聚焦显微镜、定量放射自显影、脑血流量和血脑屏障通透性的数学模型、研究神经元结构和功能的方法(例如电生理学)、行为测试和神经炎症。这项拟议的应用将填补我们对周细胞在中枢神经系统中作用的认识空白，并可能对我们理解神经退变过程和治疗具有重要意义。我们期望产生明确的数据，表明周细胞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，而成年中枢神经系统周细胞的丧失在微血管和神经元变性的发展中起着关键作用。这一数据将使脑周细胞成为治疗神经退行性疾病的主要新靶点。

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.