The Role of HIV-1 Tat in Alzheimer's Disease

HIV-1 Tat 在阿尔茨海默病中的作用

基本信息

批准号：
7582408
负责人：
Brian Giunta
金额：
$ 14.26万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-07 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582408
关键词：
AIDS Dementia Complex Address Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Anti-Retroviral Agents Apoptotic Biochemical Brain Chronic Chronic Disease Complex Congo Red Data Dementia Deposition Detection Disease Dose Endocytosis Fluorescein-5-isothiocyanate Fluorescence Microscopy Future Green tea HIV HIV Infections HIV-1 Healthcare High Prevalence Highly Active Antiretroviral Therapy Hippocampus (Brain)Immune Sera Infection Inflammation Interferon Type II Intervention LDL-Receptor Related Protein 1 Laboratories Lead Ligands Lipoprotein Receptor Longevity Measures Microglia Modeling Mus Names Neurodegenerative Disorders Neurons Pathologic Processes Pathology Patients Peptides Phagocytosis Population Process Proteins Radial Recombinants Research Personnel Role STAT1 gene Signal Transduction Synapses Techniques Testing Therapeutic Time Training Translational Research Upper arm Water Western Blotting Work aged apolipoprotein E-3 attenuation behavior test bench to bedside density early onset fluorescence microscope gallocatechol high throughput screening in vivo inflammatory marker inhibitor/antagonist mouse model neuropsychiatry neurotoxicity novel prevent programs prophylactic receptor response tat Protein uptake

项目摘要

DESCRIPTION (provided by applicant): This applications broad-long term objectives are to train in the applicant in laboratory techniques aimed at modeling/treating neurodegenerative disease. These works will be used in the future to solve an existing health care problem: the lack of current prophylactics or treatments for patients who have HIV-associated dementia (HAD); a neuropsychiatric disorder which has become a chronic disease due in large part to extension of patient life spans by highly active anti-retroviral therapy (HAART). Alzheimer's disease (AD) - like pathology in the form of toxic A(3/(3-amyloid brain deposition is a common feature of HAD, and past works as well as our preliminary data indicate a direct role for HIV-1 Tat inhibition of microglial phagocytosis of Ap peptide. Indeed it is predicted that in the future there will be a large population of HIV infected patients with comorbid AD. To study the effects of chronic HAD-like brain Tat secretion on amyloid beta formation, the following specific aims have been developed. Specific Aim (1) focuses on the creation of a novel mouse model of HAD with AD-like features. Given that HIV-1 Tat inhibits microglial uptake of A(3 (a process augmented by IFN-gamma) and the high prevalence of amyloid brain deposition in the HIV infected population, we propose to cross two previously validated AD (PSAPP mice) and HAD (GT-tg mice) mouse models. PSAPP mice develop AD-like A|3 deposits and associated inflammation while GT-tg mice demonstrate chronic brain HIV-1 Tat expression. We hypothesize this chronic HIV-1 Tat secretion will cause an early onset and increased level of A(3/(3-amyloid deposits in the brain parenchyma of PSAPP/GT-tg mice compared to PSAPP mice and littermate controls. Following behavioral testing, the AJ31-40 and A(31- 42 species will quantified in brain via fluorescence microscopy as well as western blot analysis. Compact amyloid deposits will be detected with Congo red. Apoptotic neurons, synaptic density, neuron counting, morphometric analysis of hippocampal neurons, and inflammatory markers will be quantified as well. Aim (2) tests EGCG as an intervention in vivo in the GT-tg/PSAPP mouse model. We plan to validate in vivo whether EGCG treatment can oppose Tat's effect on the above endpoints in PSAPP/GT-tg mice by intraperitoneally administering EGGG, in prophylactic and therapeutic paradigms. It is hypothesized that EGCG will confer a marked attenuation of the above described pathological end-points in PSAPP/GT-tg mice.

描述（由申请人提供）：该申请长期目标是在实验室技术中培训旨在建模/治疗神经退行性疾病的实验室技术。这些作品将来将用于解决现有的医疗保健问题：缺乏与艾滋病毒相关痴呆症患者（HAT）患者的当前预防药物或治疗方法；一种神经精神疾病，它已成为一种慢性疾病，这在很大程度上是由于高度活跃的抗网状病毒疗法（HAART）延长患者寿命的原因。阿尔茨海默氏病（AD） - 像病理学一样，有毒形式（3/（3/（3-淀粉样蛋白的脑沉积物沉积是HAD的共同特征慢性在淀粉样蛋白β形成上的大脑分泌，已经开发出以下特定目标（1）。 AD（PSAPP小鼠）具有（GT-TG小鼠）小鼠模型。 We hypothesize this chronic HIV-1 Tat secretion will cause an early onset and increased level of A(3/(3-amyloid deposits in the brain parenchyma of PSAPP/GT-tg mice compared to PSAPP mice and littermate controls. Following behavioral testing, the AJ31-40 and A(31- 42 species will quantified in brain via fluorescence microscopy as well as western blot analysis. Compact amyloid沉积物将用刚果红，神经元计数，海马神经元的形态分析，炎症标记的形态分析也将量化，并且还将量化炎症标记。 PSAPP/GT-TG小鼠在预防性和治疗性范式中通过腹膜内施用Eggg。