Dysfunctions of Sphingolipid and Sterol Metabolism in HIV-Dementia

HIV-痴呆症中的鞘脂和甾醇代谢功能障碍

• 批准号: 8071988
• 负责人: Norman J Haughey
• 金额: $ 29.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-17 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071988
• 关键词: AIDS Dementia Complex; Age-Years; Astrocytosis; Attention; Attenuated; Biochemical; Biochemistry; Brain; Calcium; Calcium Channel; Cell Surface Receptors; Cell membrane; Cellular Membrane; Ceramides; Cessation of life; Cholesterol; Clinical Trials; Cognitive; Coupling; Data; Death Domain; Dementia; Endoplasmic Reticulum; Equilibrium; Excitatory Amino Acid Receptors; Functional disorder; Gangliosides; Generations; Giant Cells; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Imaging Techniques; Impaired cognition; Kinetics; Lead; Lipid Peroxidation; Lipids; Mediating; Membrane; Membrane Microdomains; Metabolism; Modification; Molecular; Motor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neuronal Dysfunction; Neurons; Oxidants; Oxidation-Reduction; Pallor; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphorylation Site; Point Mutation; Proteins; Reporting; Research; Research Personnel; Role; Signal Transduction; Sphingolipids; Sphingomyelins; Stabilizing Agents; Sterols; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Transgenic Mice; aspartate receptor; cognitive function; design; functional group; gp-120 Antigen; improved; innovation; macrophage; neuron loss; neurotoxic; prevent; receptor; receptor density; receptor function; response; success; therapy design; trafficking; voltage; white matter

DESCRIPTION (provided by applicant): HIV-dementia is the most common form of dementia in persons under 40 years of age. Therapeutic interventions designed to improve cognitive function or to prevent further cognitive decline in patients with HIV-dementia have focused on drugs that interact with receptors such as excitatory amino acid receptors and voltage operated calcium channels. Unfortunately, clinical trials with these agents have had limited success. In this proposal we look at a common pathway that is deregulated by HIV infection. We present the first evidence that begins to identify a mechanism whereby increased levels of ceramide and cholesterol in the brains and CSF of HIV infected patients with dementia can lead to neuronal dysfunction and death. We further identify and test potential neuroprotective therapeutics that stabilize sphingolipid metabolism. The long-term goals of this research are to discover and test therapeutic agents that protect neuronal function by stabilizing sphingolipid biochemistry. Sphingomyelin, ceramide, cholesterol and ganglosides are the primary constituents of specialized membrane domains called 'lipid rafts". These specialized regions of cellular membranes are thought be important to coordinate cellular signaling by localizing functional groups of proteins in the plasma membrane and by coupling transmembrane receptors with signal transduction machinery. Lipid rafts can be modified by ceramide to form larger domains, which serve to cluster receptor molecules. The generation of a high receptor density might be required for initiation of receptor-specific signaling and has been implicated as pivotal step in the formation of "death domains". We have identified a ceramide-dependent mechanism that promotes the clustering of N-methyl-D- aspartate (NMDA) receptors into lipid rafts in response to the neurotoxic HIV-1 proteins gp120 and Tat. NMDA-evoked calcium bursts in these microdomains are sufficiently elevated to activate calcium dependent death effectors. Using biochemical, biophysical, molecular, electrophysiological and imaging techniques we propose to determine the mechanisms that direct the neurotoxic effects of the HIV-1 proteins gp120 and Tat by disrupting sphingolipid metabolism. These findings may lead to the rational design of pharmaceutical agents that are neuroprotective by mechanisms that stabilize sphingolipid metabolism and prevent the abnormal clustering of dysfunctional NMDA receptors.

描述（由申请人提供）：HIV 痴呆是 40 岁以下人群中最常见的痴呆形式。旨在改善艾滋病痴呆患者认知功能或预防进一步认知能力下降的治疗干预措施重点关注与兴奋性氨基酸受体和电压控制钙通道等受体相互作用的药物。不幸的是，这些药物的临床试验取得的成功有限。在本提案中，我们研究了一条因艾滋病毒感染而解除管制的共同途径。我们提出了第一个证据，开始确定一种机制，即艾滋病毒感染痴呆症患者大脑和脑脊液中神经酰胺和胆固醇水平升高可导致神经元功能障碍和死亡。我们进一步确定并测试稳定鞘脂代谢的潜在神经保护疗法。这项研究的长期目标是发现和测试通过稳定鞘脂生物化学来保护神经元功能的治疗药物。鞘磷脂、神经酰胺、胆固醇和神经节苷脂是称为“脂筏”的特殊膜结构域的主要成分。细胞膜的这些特殊区域被认为通过定位质膜中蛋白质的功能基团和​​偶联跨膜受体来协调细胞信号传导非常重要脂筏可以被神经酰胺修饰以形成更大的结构域，其用于聚集受体分子可能需要产生高受体密度。受体特异性信号传导，并且被认为是“死亡结构域”形成的关键步骤，我们已经确定了一种神经酰胺依赖性机制，可促进 N-甲基-D-天冬氨酸 (NMDA) 受体聚集到脂筏中以响应。利用生物化学、生物物理学、分子学等方法，神经毒性 HIV-1 蛋白 gp120 和 NMDA 引起的钙爆发被充分升高，以激活钙依赖性死亡效应器。我们建议利用电生理学和成像技术来确定通过破坏鞘脂代谢来指导 HIV-1 蛋白 gp120 和 Tat 的神经毒性作用的机制。这些发现可能有助于合理设计药物，通过稳定鞘脂代谢和防止功能失调的 NMDA 受体异常聚集的机制来保护神经。