Opiate abuse and sex steroids influence neuroAIDS pathology

阿片类药物滥用和性类固醇影响神经艾滋病病理学

• 批准号: 9761516
• 负责人: Jason Richard Paris
• 金额: $ 24.02万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761516
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Affective; Aging; Allopregnanolone; Animal Model; Animals; Anxiety; Astrocytes; Attenuated; Award; Behavior; Behavioral; Behavioral Genetics; Brain Pathology; Calcium; Cells; Chronic; Clinical Trials; Coculture Techniques; Cognition; Cognition Disorders; Cognitive; Contracts; Corpus striatum structure; Data; Dendrites; Dendritic Spines; Development; Dose; Endocrine; Enhancers; Enzymes; Estradiol; Estrogen Receptor alpha; Estrogens; Etiology; Female; Finasteride; Formestane; Gender; General Population; Gonadal Steroid Hormones; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Hormonal; Hormones; Human; Individual; Infection; Injecting drug user; Intractable Pain; Ions; MK801; Maintenance; Mediating; Membrane Potentials; Menopause; Mentors; Microglia; Mitochondria; Molecular; Moods; Morphine; Morphology; Motor; Mus; N-Methyl-D-Aspartate Receptors; National Institute of Drug Abuse; Neurons; Nitrites; Nuclear; Opioid; Opioid abuser; Outcome Measure; Pathogenicity; Pathology; Pathway interactions; Periodicity; Pharmacodynamics; Pharmacology; Phase; Physiological; Placebos; Pregnanes; Process; Production; Progesterone; Progestins; Proteins; Reactive Oxygen Species; Recording of previous events; Regulation; Research; Risk; Sex Bias; Source; Steroids; Tamoxifen; Techniques; Testing; Therapeutic; Time; Tissues; Toxic Actions; Transgenic Mice; Transgenic Organisms; Woman; age group; aged; associated symptom; biocytin; chemokine; connective tissue-activating peptide; cytokine; density; experience; experimental study; fetal; fluorescence imaging; gender difference; genetic approach; hormone therapy; immunocytochemistry; in vivo; inhibitor/antagonist; innovation; male; men; mitochondrial dysfunction; mitochondrial membrane; mouse model; mu opioid receptors; nerve stem cell; neurobehavioral; neuronal cell body; neuropathology; neuropsychiatry; neurosteroids; neurotoxicity; novel; opioid abuse; opioid use; preclinical trial; prescription opioid; programs; protective effect; receptor; relating to nervous system; sex; steroid hormone; translational approach; transmission process

Individuals with human immunodeficiency virus (HIV) experience brain pathology associated with greater motor/mood/cognitive disorders (collectively termed "neuroAIDS") than the general population and these effects are exacerbated among opiate abusers. Moreover, gender differences exist with opiate-abusing women at greater risk to contract HIV compared to opiate-abusing men; yet, some women may experience lesser neuroAIDS symptomology than men once infection occurs. We recapitulated these effects in mice and have begun to elucidate the sex steroid hormones that interact with opiates to confer protection to neuroAIDS. The present proposal will begin to reveal the effects and mechanisms of sex steroid interactions with opiates and HIV in a translational approach that utilizes cultured murine and human neural cells, as well as transgenic whole-animal murine models. This Pathway to Independence Award (K99/R00) will begin to discern the cellular/molecular mechanisms by which sex steroid milieu may influence opiate/HIV interactions for neuroAIDS pathology. In the R00 independent phase of this grant, we will examine the protective effects of central steroid formation on opiate/HIV protein interactions in vivo using whole-animal models that conditionally-express central HIV-1 Tat (Aim 3a) or constitutively-express central gp120 (Aim 3b). Neurosteroid formation will be pharmacologically inhibited or facilitated in male and female mice and subjects will be assessed for neuroAIDS-like motor, affective, and cognitive behavior. Striatal tissue will be assessed for viable/degenerating neurons, astrocytes, and microglia via immunocytochemistry and viable striatal medium spiny neurons (MSNs) will be assessed for sublethal changes in morphology. The influence of pharmacodynamic targets that overlap between steroids, opiates, X4/R5-tropic HIV, and HIV proteins (Tat or gp120) will be examined in murine neural co-cultures obtained mice and differentiated fetal neural progenitor cells (Aim 3c). Cultures will be pretreated with pharmacological antagonists to NMDA receptors, mGluR1, estrogen receptors (alpha and beta), and mu opioid receptors. As in the prior K99 project (Aims 1-2), cultures will be assessed for MSN morphology, intracellular ion concentrations ([Ca2+]i and [Na+]i) within MSN soma and dendrites, and mitochondrial membrane potential (via JC-10 fluorescence imaging). Supernatants will be assessed for production of cytokines/chemokines, reactive oxygen species, and nitrites. This proposal enables the development of an innovative and independent research program.

人类免疫缺陷病毒（HIV）感染者的大脑病理学与更大的 运动/情绪/认知障碍（统称为“神经艾滋病”）比一般人群和这些 鸦片剂滥用者的影响更为严重。此外，滥用阿片类药物的妇女存在性别差异， 与滥用阿片类药物的男性相比，女性感染艾滋病毒的风险更大;然而，一些女性可能会经历更少的风险。 神经艾滋病患者比男性一旦发生感染。我们在小鼠中重现了这些效应， 开始阐明性类固醇激素与阿片类药物相互作用以保护神经艾滋病。的 本提案将开始揭示性类固醇与阿片类药物相互作用的作用和机制， 利用培养的鼠和人神经细胞以及转基因细胞， 全动物鼠模型。这个独立之路奖（K99/R 00）将开始辨别 性类固醇环境可能影响阿片类药物/HIV相互作用的细胞/分子机制 神经艾滋病病理学在R 00独立阶段，我们将研究 使用整体动物模型， 条件性表达中心HIV-1达特（Aim 3a）或组成性表达中心gp 120（Aim 3b）。神经类固醇 将在雄性和雌性小鼠中抑制或促进血管生成， 评估神经艾滋病样运动，情感和认知行为。将评估纹状体组织的 通过免疫细胞化学和存活纹状体培养基检测存活/退化神经元、星形胶质细胞和小胶质细胞 评估棘神经元（MSN）的亚致死形态变化。的影响 类固醇、阿片类药物、X4/R5嗜性HIV和HIV蛋白（达特或 gp 120）将在获得的鼠神经共培养物中检测小鼠和分化的胎儿神经祖细胞 细胞（Aim 3c）。将用NMDA受体的药理学拮抗剂mGluR 1预处理培养物， 雌激素受体（α和β）和μ阿片受体。与之前的K99项目（目标1-2）一样， 将评估MSN形态学、MSN索马内的细胞内离子浓度（[Ca 2 +]i和[Na+]i 树突和线粒体膜电位（通过JC-10荧光成像）。上清液将 评估细胞因子/趋化因子、活性氧和亚硝酸盐的产生。该提案使 发展创新和独立的研究计划。