AIBP and regulation of neuropathic pain

AIBP 和神经性疼痛的调节

基本信息

批准号：
9816541
负责人：
Yury Miller
金额：
$ 78.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816541
关键词：
Acute Affect Affinity Agonist American Apolipoprotein A-I Arthritis Binding Binding Proteins Cell membrane Cellular Membrane Cholesterol Cisplatin Development Diabetes Mellitus Dimerization Event Excision HIV Inflammatory Inflammatory Response Intrathecal Injections Knock-out Lead Ligands Mediating Membrane Microdomains Microglia Molecular Mus Mutate Neuroglia Pattern Persistent pain Quality of life Receptor Inhibition Recombinants Regulation Role Signal Transduction Sphingomyelins Spinal Cord TLR4 gene Tactile Testing Therapeutic Variant Work allodynia base chemotherapy experimental study glial activation in vivo mouse model neuroinflammation novel therapeutic intervention novel therapeutics painful neuropathy prevent receptor receptor function

Acute Affect Affinity Agonist American Apolipoprotein A-I Arthritis Binding Binding Proteins Cell membrane Cellular Membrane Cholesterol Cisplatin Development Diabetes Mellitus Dimerization Event Excision HIV Inflammatory Inflammatory Response Intrathecal Injections Knock-out Lead Ligands Mediating Membrane Microdomains Microglia Molecular Mus Mutate Neuroglia Pattern Persistent pain Quality of life Receptor Inhibition Recombinants Regulation Role Signal Transduction Sphingomyelins Spinal Cord TLR4 gene Tactile Testing Therapeutic Variant Work allodynia base chemotherapy experimental study glial activation in vivo mouse model neuroinflammation novel therapeutic intervention novel therapeutics painful neuropathy prevent receptor receptor function

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项目摘要

Project Summary Persistent pain states, arising from inflammatory conditions, such as in arthritis, diabetes, HIV, and chemotherapy among others, have an extraordinary negative impact on quality of life. A common feature of these initiating events is the release of damage-associated molecular pattern (DAMP) molecules, which can activate Toll-like receptor-4 (TLR4). Our previous studies suggest that TLR4 is critical in mediating the transition from acute to persistent pain. TLR4 as well as other inflammatory receptors localize to lipid raft microdomains on the plasma membrane. Lipid rafts, enriched with cholesterol and sphingomyelin, facilitate ligand-mediated receptor dimerization and downstream signaling. Removal of cholesterol from the plasma membrane reduces lipid rafts and often results in inhibition of receptor function. We have found that the secreted apoA-I binding protein (AIBP) accelerates cholesterol removal, disrupts lipid rafts, prevents TLR4 dimerization and inhibits microglia inflammatory responses to LPS. Furthermore, because AIBP binds to TLR4 and its affinity increases when TLR4 is activated by an agonist, we propose that AIBP targets cholesterol removal to lipids rafts harboring activated TLR4. In our recent work, we have also found that this mechanism is relevant to regulation of neuropathic pain states. Intrathecal injections of recombinant AIBP prevented LPS-induced tactile allodynia and, remarkably, reversed established cisplatin-induced allodynia. Based on these findings, we propose that targeted, AIBP- mediated disruption of lipid rafts and its effects upon TLR4 signaling can be a potential therapeutic strategy in treating neuropathic pain states. The Specific Aims of this proposal are: (1) to test the hypothesis that AIBP targets lipid rafts harboring activated TLR4; (2) to test the hypothesis that AIBP reduces glial activation and neuroinflammation in mouse models of neuropathic pain; and (3) to identify the origin and function of endogenous AIBP in the spinal cord. To test these hypothesis, we propose experiments, in vivo and in isolated glial cells, to elucidate the AIBP-TLR4 binding and lipid raft mechanism, and to characterize glial activation and neuroinflammation states. We will also make AIBP variants with mutated apoA-I or TLR4 binding interfaces to validate the proposed mechanism. Using our unique AIBP knockout and AIBP flox/flox mice, we will identify the role of endogenous AIBP in lipid raft regulation and neuroinflammation. In summary, our proposed experiments will elucidate the mechanisms by which AIBP reduces neuroinflammation and alleviates neuropathic pain. Our studies may also suggest that raising AIBP levels in the CNS may be a novel therapeutic approach to treat persistent pain states.

项目摘要持续性疼痛状态，由炎症状况（例如关节炎，糖尿病，艾滋病毒和化学疗法在其他方面对生活质量产生极大的负面影响。这些的共同特征引发事件是释放与损伤相关的分子图案（DAMP）分子的释放，可以激活 Toll样受体-4（TLR4）。我们以前的研究表明，TLR4对于中介从急性疼痛。 TLR4以及其他炎症受体定位于脂质筏微区域质膜。富含胆固醇和鞘磷脂的脂质筏有助于配体介导的受体二聚和下游信号传导。从质膜中除去胆固醇可减少脂质筏通常导致受体功能的抑制。我们发现分泌的ApoA-I结合蛋白（AIBP）加速胆固醇去除，破坏脂质筏，防止TLR4二聚化并抑制小胶质细胞对LP的炎症反应。此外，因为AIBP与TLR4结合，其亲和力在TLR4时增加被激动剂激活，我们提出AIBP靶向胆固醇去除脂质的木筏，该脂质饲养已激活 TLR4。在我们最近的工作中，我们还发现这种机制与神经性疼痛的调节有关国家。重组AIBP的鞘内注射可阻止LPS诱导的触觉异常性异常，显着，逆转了已建立的顺铂诱导的异常性疾病。基于这些发现，我们建议针对AIBP- 脂质筏的介导破坏及其对TLR4信号的影响可能是潜在的治疗策略治疗神经性疼痛状态。该提案的具体目的是：（1）检验AIBP的假设靶脂筏具有活化的TLR4；（2）检验AIBP降低神经胶质激活和的假设神经性疼痛的小鼠模型中的神经炎症；（3）确定内源性的起源和功能 AIBP在脊髓中。为了检验这些假设，我们建议在体内和孤立的神经胶质细胞中进行实验阐明AIBP-TLR4结合和脂质筏机制，并表征神经胶质激活和神经炎症状态。我们还将使用突变的ApoA-I或TLR4结合接口进行AIBP变体验证提出的机制。使用我们独特的AIBP敲除和AIBP Flox/Flox小鼠，我们将确定内源性AIBP在脂质筏调节和神经炎症中的作用。总而言之，我们提出的实验将阐明AIBP减少神经炎症并减轻神经性疼痛的机制。我们的研究还可能表明，在中枢神经系统中提高AIBP水平可能是一种治疗的新型治疗方法持续的疼痛状态。