MMPS IN HIV DEMENTIA: EFFECTS ON BBB STRUCTURE/FUNCTION

描述：HIV痴呆（HIVD）的病理生物学仅部分了解， 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改变已经被证实。 检测到与HIVD相关，预计这些变化将 促进炎症细胞和血清衍生毒素的进入。 细胞外基质蛋白，包括那些对细胞生长至关重要的蛋白。 血脑屏障的完整性，是由一个内源性的蛋白质家族， 基质金属蛋白酶（MMP）。这些蛋白酶不仅由 活化的T细胞和单核细胞，因为它们迁移通过BBB，但也通过 脑实质的常驻细胞。已经表明，注射 MMPs进入脑实质导致BBB破坏， 随后是中枢神经系统（CNS）的白细胞浸润。 此外，脑实质内产生的MMPs可能具有更直接的 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以及神经元存活。 在本研究中，我们将讨论激活和HIV-1的可能性， 受感染的单核细胞释放物质，这些物质反过来可以增加 来自CNS驻留细胞的MMP。我们还将讨论以下可能性： 来自活化的和HIV感染的单核细胞的上清液，以及MMP 它们诱导的这些变化将影响体外BBB的结构和功能 模型这些研究是新颖的，因为来自 激活和HIV感染的单核细胞对MMP产生的驻留细胞的 CNS是未知的，一般来说，对MMP在CNS中的调节知之甚少。 CNS。此外，拟议的研究将使用原发性脑源性艾滋病毒 分离物，其不同于实验室适应菌株，和正常人细胞， 其也显著不同于啮齿动物或肿瘤来源的那些。

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.