MMPs, Integrins and Microglial activation in HAND

HAND 中的 MMP、整合素和小胶质细胞激活

• 批准号: 8334881
• 负责人: Katherine E Conant
• 金额: $ 23.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-21 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334881
• 关键词: Area; Biological Assay; Brain; Cadherins; Cell Adhesion Molecules; Cell surface; Cells; Cerebrospinal Fluid; Co-Immunoprecipitations; Data; Demyelinations; Disease; Disease model; Encephalitis; Goals; Grant; HIV; HIV Envelope Protein gp120; Immunoglobulin Domain; Immunologic Deficiency Syndromes; In Vitro; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Injury; Integrin Binding; Integrins; Ligands; Ligation; Link; Lipopolysaccharides; Macrophage-1 Antigen; Mass Spectrum Analysis; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediating; Microglia; Midbrain structure; Minocycline; Molecular; Morphology; Neuronal Injury; Neurons; Patients; Peptide Hydrolases; Phagocytosis; Phenotype; Play; Production; Proteins; Publications; Publishing; Reactive Oxygen Species; Role; Sampling; Signal Transduction; Stimulus; Synapses; TNF gene; Techniques; Testing; Transgenic Animals; Virus Diseases; base; cell fixing; cell type; clinically relevant; dopaminergic neuron; in vivo; intercellular cell adhesion molecule; interest; migration; nervous system disorder; neurotoxicity; protein protein interaction; receptor; research study; response; single molecule

DESCRIPTION (provided by applicant): Classical microglial activation may contribute to neuronal injury occurring with HIV associated neurological disorders (HAND). Emerging evidence suggests that matrix metalloproteinases (MMPs) could play a critical role in stimulating such activation. For example, inhibition of MMP activity blocks microglial activation in response to stimuli including lipopolysaccharide. In addition, minocycline, a potent inhibitor of MMP expression and activity, abrogates microglial activation occurring with osmotic demyelination as well as with simian immunodeficiency viral (SIV) infection. The mechanisms by which MMPs might activate microglia are not completely understood. Of interest, however, is the potential for MMPs to generate ligands for integrins that are highly expressed on microglia. Integrin dependent signaling can in turn stimulate changes associated with an activated phenotype. That this mechanism could be important is underlined by data showing that inhibition of microglial integrin expression, or function, blocks microglial phagocytosis and migration. In addition, recent studies have shown that select integrin antagonists can substantially reduce microglial activation and associated neurotoxicity in more than one disease model. In previous publications we have shown that HIV proteins can increase MMP release from brain derived cells, and that MMP levels are increased in spinal fluid samples from patients with HAND. In the present application, we hypothesize that these MMPs generate specific cell adhesion molecule (CAM) fragments that will in turn engage microglial integrins. Our focus on CAM fragments is based on several considerations. CAMs are easily accessible by virtue of their proximity to the cell surface, an area where MMP activity may be concentrated. We and others have shown that MMPs stimulate ectodomain shedding of these molecules, and elevated levels of soluble forms can be detected in spinal fluid samples from patients with brain inflammation. Moreover, we have recently published data showing that the shed domain of at least one CAM can interact with a microglial integrin that has been well linked to an activated phenotype. In the present R21 proposal we plan to identify microglial integrin-binding ligands that may be increased in association with HIV, to investigate the hypothesis that these ligands stimulate classical, pro-inflammatory microglial activation, and to determine whether this activation is of sufficient magnitude to be inimical to vulnerable neurons. We will focus on CAMs that are widely expressed in the CNS, including the immunoglobulin (Ig) domain containing intercellular cell adhesion molecules (ICAMs) and synaptic CAMs (synCAMs), as well as the cadherins. We will also focus on integrins that mediate microglial activation in other disease models, such as LFA-1 and Mac- 1. This dual PI grant relies on expertise related to MMPs (KC), as well as microglia and dopaminergic neurons (KMZ). The possibility that MMPs contribute to microglial activation in the setting of HIV is yet untested and clinically relevant, in that it would allow MMP inhibitor to be used in an attempt to reduce such activation. Further study of the receptors that underlie MMP dependent effects is also clinically relevant. At least one soluble CAM can interact with LFA-1, a microglial integrin for which a clinically tolerable antagonist has been developed. PUBLIC HEALTH RELEVANCE: Microglial activation has been linked to neurotoxicity in varied disease models. Understanding whether proteases and integrins contribute to microglial activation in the setting of HIV disease may allow us to test specific antagonists for their abilit to reduce HIV associated neurological disease.

描述（由申请人提供）：经典的小胶质细胞激活可能会导致与HIV相关的神经系统疾病（HAND）发生的神经元损伤。新兴的证据表明，基质金属蛋白酶（MMP）在刺激这种激活中起关键作用。例如，对MMP活性的抑制会阻止小胶质细胞激活对包括脂多糖在内的刺激。此外，米诺环素是一种有效的MMP表达和活性抑制剂，它消除了渗透脱髓鞘以及Simian免疫缺陷病毒（SIV）感染的小胶质细胞活化。 MMP可能激活小胶质细胞的机制尚不完全了解。然而，有趣的是，MMP的潜力产生了在小胶质细胞上高度表达的整联蛋白的配体。整合素依赖性信号转导可以刺激与激活表型相关的变化。该机制可能很重要的是，数据表明抑制小胶质细胞整合素表达或功能会阻止小胶质细胞增多症和迁移。此外，最近 研究表明，在多种疾病模型中，精选的整联蛋白拮抗剂可以大大降低小胶质细胞激活和相关的神经毒性。 在先前的出版物中，我们已经表明，艾滋病毒蛋白可以增加从脑衍生细胞中释放的MMP，并且在脊柱液样品中，MMP水平升高。在本应用中，我们假设这些MMP会产生特定的细胞粘附分子（CAM）片段，而小胶质细胞整联蛋白会依次参与。我们对凸轮碎片的关注是基于几个考虑因素。凸轮可以通过靠近细胞表面的凸轮来访问，该区域可能会浓缩MMP活性。我们和其他人表明，MMP刺激这些分子的外域域脱落，并且可以在脑炎患者的脊髓液样品中检测到可溶性形式的升高。此外，我们最近发布了数据，表明至少一个CAM的棚结构域可以与已与活化表型充分链接的小胶质细胞整合素相互作用。 在目前的R21提案中，我们计划鉴定可能与HIV相关的小胶质细胞整合素结合配体，以研究这些配体刺激经典的，促炎的小胶质细胞激活的假设，并确定这种激活是否足够大量量足以使脆弱的神经元具有不利的脆弱神经元。我们将专注于在中枢神经系统中广泛表达的CAM，包括包含细胞间细胞粘附分子（ICAMS）和突触凸轮（Syncams）的免疫球蛋白（IG）结构域以及钙粘蛋白。我们还将专注于在其他疾病模型中介导小胶质细胞激活的整合素，例如LFA-1和MAC-1。此双PI赠款依赖于与MMPS（KC）以及小胶质细胞和多巴胺能神经元（KMZ）相关的专业知识。 MMP在HIV中有助于小胶质细胞激活的可能性尚未经过测试且临床相关，因为它将允许MMP抑制剂用于减少这种激活。对基础MMP依赖性作用的受体的进一步研究也与临床相关。至少一个可溶性凸轮可以与LFA-1相互作用，LFA-1是一种小胶质细胞整合蛋白，已经开发了临床上可耐受的拮抗剂。 公共卫生相关性：小胶质细胞激活与各种疾病模型中的神经毒性有关。了解蛋白酶和整联蛋白是否有助于在HIV疾病的情况下有助于小胶质细胞激活，这可能使我们能够测试特定的拮抗剂，以减少与HIV相关的神经系统疾病。