AIDS-RELATED CHANGES IN THE BLOOD-BRAIN BARRIER

虽然艾滋病病毒引起的病理相关性 神经系统疾病知之甚少，最近的证据表明， 血脑屏障（BBB）的改变有助于 艾滋病引起的痴呆症的进展。 血清成分流入 中枢神经系统可以通过改变神经元的功能来损害神经元的功能。 微观环境。 HIV感染者有全身异常， 例如免疫激活和细胞因子水平升高， 并产生神经元功能障碍和最终神经元死亡。 本研究的总体目标是确定 BBB改变与神经系统疾病的进展有关， 艾滋病毒感染。 具体目标1将定义BBB损伤的程度 并将这种损害与临床和 患者的免疫状态。 如果BBB发生变化， 导致HIV感染者的神经系统疾病， 可以通过预防BBB损伤的疗法来预防或延迟疾病。 因此，具体目标2-4中的研究将确定以下方面的变化： 内皮细胞和血管周围的巨噬细胞，有助于血脑屏障 功能障碍，而特定目标5将表征 神经元 初步研究表明，一氧化氮（NO）的产生是 在HIV感染的大脑的内皮细胞中表达上调。 内皮NO 是一种血管扩张剂和毒素，可以改变血脑屏障的通透性。 由于NO难以测量，因此NO合成细胞将被抑制。 通过定位NO代谢酶一氧化氮 合成酶（NOS）。 至少有四种不同形式的NOS存在于 个脑袋 具体目标2将决定 这些不同的NOS分子。 我们将确定 如果NOS表达的增加与BBB的改变相关， 患有痴呆症 本提案的具体目标3将体现以下特点： HIV感染者大脑中内皮细胞粘附分子的表达。 是 预期内皮细胞会改变基因的表达， 已知是可诱导的或对病理条件有反应的。 我们将确定ICAM、VCAM和ELAM的表达是否在 内皮细胞的损伤与BBB的破坏或痴呆有关。 这些 粘附分子可以结合单核细胞， 进入感染艾滋病病毒的大脑 具体目标4将 关注HIV感染者血管周围巨噬细胞的特征 个脑袋 我们将确定这些细胞的数量是否 艾滋病毒感染的增加，以及其增加是否与 BBB的改变或痴呆。 此外，我们将确定 血管周围巨噬细胞表达可检测水平的 HIV蛋白和细胞因子如TNF-α和IL-1 β。 是 预计内皮细胞的改变将先于 神经功能障碍和可检测的BBB变化。 具体目标 5将使神经元病理学的发展与 内皮细胞、BBB破坏和痴呆的发展。

Although the pathological correlates responsible for HIV-induced neurological disease are poorly understood, recent evidence suggests that alterations in the blood-brain barrier (BBB) contribute to the progression of HIV-induced dementia. Influx of serum components into the central nervous system could compromise neuronal function by altering the micro-environment. HIV-infected individuals have systemic abnormalities, such as immune activation and elevated cytokine levels, that could alter the BBB and produce neuronal dysfunction and eventual neuronal death. The overall objective of this study is to determine the contribution of altered BBB to the progression of neurological diseases associated with HIV infection. Specific Aim 1 will define the extent of BBB damage during HIV infection and correlate this damage with the clinical and immunological status of the patient. If alterations in the BBB contribute to neurologic disease in HIV-infected individuals, such disease may be prevented or delayed by therapies that prevent BBB damage. Therefore, the studies in Specific aims 2-4 will define changes in endothelial cells and perivascular macrophages that contribute to BBB dysfunction, whereas Specific Aim 5 will characterize alterations in neurons. Preliminary studies indicate that production of nitric oxide (NO) is upregulated in endothelial cells of HIV-infected brains. Endothelial NO is a vasodilator and toxin that can alter the permeability of the BBB. Because NO is difficult to measure, NO synthesizing cells will be identified by localizing the NO metabolizing enzyme, nitric oxide synthase (NOS). At least four different forms of NOS are present in brain. Specific Aim 2 will determine the distribution and quantity of these different NOS molecules in HIV-infected brains. We will determine if increases in NOS expression correlate with alterations in the BBB or with dementia. Specific Aim 3 of this proposal will characterize the expression of adhesion molecules by endothelial cells in HIV-infected brains. It is anticipated that endothelial cells will alter the expression of genes that are known to be inducible or to respond to pathological conditions. We will determine if the expression of ICAM, VCAM, and ELAM on endothelial cells is related to breakdown of the BBB or dementia. These adhesion molecules can bind monocytes and they may facilitate the entry of perivascular macrophages into HIV-infected brain. Specific Aim 4 will focus on the characterization of perivascular macrophages in HIV-infected brain. We will determine whether the numbers of these cells are increased in HIV infection and whether their increase correlates with alterations in the BBB or with dementia. In addition, we will determine what percentage of perivascular macrophages express detectible levels of HIV protein and cytokines such as TNF-alpha and IL-1beta. It is anticipated that alterations in endothelial cells will precede neurological dysfunction and detectible changes in the BBB. Specific Aim 5 will correlate the development of neuronal pathology with changes in endothelial cells, BBB breakdown, and development of dementia.