MMPS IN HIV DEMENTIA: EFFECTS ON BBB STRUCTURE/FUNCTION

描述：HIV痴呆症(HIVD)的病理生物学还只有部分了解， 然而，有证据表明血脑屏障(BBB)的破坏可能 发挥作用。血脑屏障的结构和功能变化 在与HIVD相关的情况下被检测到，这些改变预计会 促进炎症细胞和血清衍生毒素的进入。 细胞外基质蛋白，包括那些对 血脑屏障的完整性，由一个内源性蛋白质家族调节，称为 基质金属蛋白酶(MMPs)。这些蛋白水解酶不仅由 活化的T细胞和单核细胞通过血脑屏障迁移，但也通过 脑实质的常驻细胞。已有研究表明，注射 进入大脑实质的MMPs会导致血脑屏障的破坏，这是 其次是中枢神经系统(CNS)的白细胞感染。 此外，在脑实质中产生的基质金属蛋白酶可能有更直接的 细胞外基质蛋白对中枢神经系统结构和功能的影响 已知会影响突触结构和神经元存活。 在本研究中，我们将讨论激活的和HIV-1 受感染的单核细胞释放物质，进而增加释放 来自中枢神经系统驻留细胞的基质金属蛋白酶。我们还将解决这样一种可能性 活化的和感染艾滋病毒的单核细胞的培养上清，以及基质金属蛋白酶 会影响体外血脑屏障的结构和功能 模特。这些研究是新颖的，因为来自于 活化和HIV感染的单核细胞对小鼠单核细胞分泌基质金属蛋白酶的影响 中枢神经系统是未知的，总的来说，对基质金属蛋白酶在血管内皮细胞中的调控知之甚少 中枢神经系统。此外，拟议的研究将使用两种主要的脑源性艾滋病毒 不同于实验室适应的菌株的分离株，以及正常的人类细胞， 这也与啮齿动物或肿瘤来源的基因有显著不同。

DESCRIPTION: The pathobiology of HIV dementia (HIVD) is only partly understood, however, evidence suggests that disruption of the blood brain barrier (BBB) may play a role. Structural and functional alterations in the BBB have been detected in association with HIVD, and these alterations would be expected to facilitate the ingress of both inflammatory cells and serum-derived toxins. Extracellular matrix proteins, including those which are critical to the integrity of the BBB, are regulated by an endogenous family of proteins called matrix metalloproteases (MMPs). These proteases are released not only by activated T cells and monocytes as they migrate through the BBB, but also by resident cells of the brain parenchyma. It has been shown that injection of MMPs into the parenchyma of the brain causes a disruption of the BBB, which is followed by leukocytic inflitration of the central nervous system (CNS). Moreover, MMPs produced within the brain parenchyma may have more direct effects on CNS structure and function in that extra cellular matrix proteins are known to affect synaptic structure as well as neuronal survival. In the present study, we will address the possibility that activated and HIV-1 infected monocytes release substances which can in turn increase the release of MMPs from resident cells of the CNS. We will also address the possibility that supernatants from activated and HIV-infected monocytes, as well as the MMPs that they induce, will affect the structure and function of an in vitro BBB model. These studies are novel in that the effects of supernatants from activated and HIV infected monocytes on MMP production by resident cells of the CNS are unknown, and in general, little is known about MMP regulation in the CNS. Also, the proposed studies will use both primary brain-derived HIV isolates, which differ from laboratory adapted strains, and normal human cells, which also differ significantly from those of rodent or tumor origin.