The role of pericytes in the adult and the aging brain

描述（由申请人提供）：周细胞是神经血管单位的基本细胞。它们嵌入脑毛细血管的血管膜内，与内皮直接局部接触。长期以来，周细胞的存在和作用一直被忽视。内皮细胞和周细胞之间的相互作用对毛细血管壁的正常功能至关重要。在胚胎中枢神经系统中，周细胞在微循环的发育中起着关键作用。尽管如此，该领域仍处于充分理解和欣赏脑周细胞生物学及其对神经系统疾病的影响的开端。该研究的主要目的是确定成人和衰老大脑中周细胞缺乏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，这对正常的大脑表现至关重要。我们假设，成人大脑中周细胞的丢失通过两个平行途径导致进行性年龄依赖性血管损伤：(1)大脑微循环减少导致毛细血管灌注减少，局部CBF减少和缺氧组织损伤；(2)血脑屏障破坏导致脑内积聚一些神经毒性和血管毒性大分子。接下来，我们假设成人大脑的周细胞丢失导致微血管变性和血管介导的继发性神经退行性改变，随后是普遍的炎症反应。为了验证我们的假设，我们建议使用以下3种脑血管发育不全模型：(1)CNS周细胞的遗传性胚胎缺失和PDGFR¿全球缺失（即F7突变体）；(2)成年CNS周细胞的诱导缺失，周细胞信号通路完整(即NG2-Cre；Pdgfr¿DTR小鼠)和(3)原发性脑内皮发育不全，其中周细胞保持完整（即Meox2+/-小鼠），作为基因完整的Pdgfr¿信号传导的非周细胞缺乏性发育不全模型。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、脑血流和血脑屏障通透性的数学建模、研究神经元结构和功能的方法（如电生理学）、行为测试和神经炎症。提出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，并可能对我们理解神经退行性过程及其治疗具有重要意义。我们期望得到明确的数据，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，并且成人中枢神经系统周细胞的缺失在微血管和神经元变性的发展中起着关键作用。这一数据应该确立脑周细胞作为神经退行性疾病的主要新治疗靶点。

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. PUBLIC HEALTH RELEVANCE: The annual health care costs for neurodegenerative disorders range in excess of a hundred billion dollars. Sadly, we do not have cure yet for any of these diseases. Understanding the role of pericytes in the adult and the aging brain will have profound implications for our understanding of neurological disorders and may ultimately guide the development of new therapeutic approaches for brain disorders.