Hiv-1 Infection: Central Serotonergic Activity and its Health Implications

HIV-1 感染：中枢血清素活性及其健康影响

• 批准号: 7849019
• 负责人: ADARSH M KUMAR
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849019
• 关键词: AIDS/HIV problem; Adherence; Adult; Affect; African American; Age; Amygdaloid structure; Area; Attenuated; Autopsy; Basal Ganglia; Beck depression inventory; Behavior; Behavioral; Biogenic Amines; Brain; Brain Stem; Brain region; Caucasians; Caucasoid Race; Cells; Cessation of life; Complex; Consent; Data; Development; Disease; Disease Progression; Ethnic group; Etiology; Focal Infection; Functional disorder; Future; Globus Pallidus; HIV-1; Health; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Hispanics; Human; Hydroxyindoleacetic Acid; Hypothalamic structure; Impairment; In Vitro; Individual; Infection; Intervention; Invaded; Investigation; Life; Life Expectancy; Mental Depression; Mental Health; Morbidity - disease rate; National NeuroAids Tissue Consortium; Nerve Degeneration; Neuraxis; Neurobiology; Neurocognitive; Neurons; Neuropathogenesis; Paroxetine; Penetration; Peripheral; Pharmaceutical Preparations; Physiological; Play; Quality of life; RNA; Regulation; Reporting; Risk Factors; Role; Sampling; Serotonin; Substantia nigra structure; System; Testing; Tissue Sample; Tissues; United States National Institutes of Health; Viral Load result; Virus; Woman; adverse outcome; assault; brain tissue; caudate nucleus; design; frontal lobe; improved; inhibitor/antagonist; men; mortality; nervous system disorder; neuronal cell body; neuropsychiatry; progressive neurodegeneration; public health relevance; putamen; raphe nuclei; reuptake; serotonin receptor; treatment strategy; viral RNA

DESCRIPTION (provided by applicant): This R21 exploratory application tests the hypothesis that the serotonergic activity will be adversely impacted in different brain regions of HIV-1+ cases. HIV-1 enters the central nervous system (CNS) immediately after initial infection and localizes itself with variable concentration in different brain regions, resulting in progressive neurodegeneration. It is proposed that HIV-1 induced degeneration of neurons of high monoaminergic activity, such as that of serotonin (5- hydroxytryptamine, 5-HT) may have a wide range of health implications, including depression and other neuropsychiatric disorders, neurological abnormalities, and neurocognitive impairment. Depression is one of the most common neuropsychiatric disorders in a large number of HIV-1 infected individuals, and affects their quality of life, interferes in adherence to treatment, and is a risk factor for disease progression, and mortality. The etiology of depression in HIV-1 infection is found to be complex and may involve a number of contributing factors including dysfunctions of neurobiological systems particularly, the central serotonin system. However, to date, investigations on the central serotonergic mechanisms and their relationship with depression in HIV-1 infection has remained under investigated and poorly understood. In order to investigate the central serotonergic mechanisms in HIV-1 infected individuals, the postmortem brain tissues, as well as the data related with assessment of depression during life of the corresponding individuals are required. In recent years, both of these requirements have been accomplished by the brain banks established by the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC), which has made possible the availability of well characterized samples of different brain regions of HIV-1+ and HIV-1- cases, and has provided the opportunity for investigations such as those proposed in this project. It is proposed to investigate the central serotonergic activity in the postmortem tissue samples from different brain regions {raphe nuclei, hypothalamus, hippocampus, basal ganglia (caudate nucleus, putamen, globus pallidus), substantia nigra, amygdala and fronto-cortical regions (cingulate and subgenual cortical areas) as well as CSF} of a total of 40 adult men and women (HIV-1+ cases, N=25; HIV-1- cases N=15), age 25-55 years, belonging to the three ethnic groups (Caucasian, African Americans, Hispanics), who consented during life to participate in the NNTC project. It is hypothesized that the levels of 5-HT as well as its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) will be decreased in the above mentioned brain regions of HIV-1+ cases, compared to that in the same brain regions of HIV-1- cases; and that the 5-HT and 5-HIAA levels will be negatively correlated with the viral load in the same brain regions of HIV-1+ cases, as well as with depression scores assessed during life of the corresponding HIV-1+ individuals. We propose to examine the 5-HT and 5-HIAA levels in these brain regions of HIV-1+ individuals who were assessed during life, at least six months before death, for depression using Beck Depression Inventory (BDI), and investigate the relationship between the central regional 5-HTactivity and viral load in the same brain regions of HIV-1+ individuals, who were treated or not treated with HAART during life. The findings from this exploratory R-21 project will delineate the specific regional vulnerability to assault by HIV-1 with respect to 5-HT activity. Furthermore, the data will provide us with an opportunity for an RO1 application to investigate the other parameters of serotonergic mechanisms including 5-HT-receptors and 5-HT transporter/s in different brain regions of HIV-1 infected cases, and for exploring the possibility for new relevant strategies for treatment. PUBLIC HEALTH RELEVANCE: This R-21 proposal explores the impact of HIV-1 infection on the central nervous system serotonergic activity in different regions of post mortem brains of HIV/AIDS cases. It is proposed that HIV-1 induces neurodegeneration of various areas of the brain that are involved in serotonergic activity. We will determine the levels of 5-HT and its metabolite, 5-HIAA in the brain stem raphe nuclei, where the cell bodies of serotonergic neurons are located and 5-HT is synthesized, as well as in various other regions which are highly innervated with serotonergic projections, and are involved in a number of physiological and behavioral functions. The findings from this study will significantly enhance our understanding of the impact of HIV-1 induced central serotonergic deficits, that may be helpful in designing the intervention strategies that will contribute to modify the central serotonergic activity, and improve the quality of life of HIV-1 infected individuals.

描述（由申请人提供）：此R21探索性申请检验以下假设：在HIV-1+病例的不同大脑区域中，血清素能活性将受到不利影响。初次感染后立即进入中枢神经系统（CNS），并在不同的大脑区域中以可变的浓度定位，从而导致进行性神经变性。有人提出，HIV-1诱导的高单胺能活性神经元的变性，例如5-羟色胺（5-羟色胺，5-HT）的神经元可能具有广泛的健康影响，包括抑郁症和其他神经精神障碍，神经学障碍，神经学的异常和神经认知感。抑郁症是大量HIV-1感染个体中最常见的神经精神疾病之一，会影响其生活质量，干扰依从性治疗，并且是疾病进展和死亡率的危险因素。发现HIV-1感染中抑郁症的病因很复杂，可能涉及许多促成因素，包括神经生物学系统的功能障碍，尤其是中央5-羟色胺系统。然而，迄今为止，对中央血清素能机制的调查及其与HIV-1感染中抑郁症的关系一直受到研究且了解不足。 为了研究HIV-1感染个体中的中央血清素能机制，后尸体脑组织以及与评估相应个体生命期间抑郁症相关的数据。近年来，这两种要求都是由NIH赞助的国家神经辅助组织（NNTC）建立的大脑库（NNTC）实现的，这使得HIV-1+和HIV-1案例的不同大脑区域的良好表征样本的可用性，并为这些项目提供了调查的机会。 It is proposed to investigate the central serotonergic activity in the postmortem tissue samples from different brain regions {raphe nuclei, hypothalamus, hippocampus, basal ganglia (caudate nucleus, putamen, globus pallidus), substantia nigra, amygdala and fronto-cortical regions (cingulate and subgenual cortical areas) as well as CSF} of a共有40名成年男女（HIV-1+病例，n = 25; HIV-1-病例n = 15），年龄在25-55岁之间，属于三个族裔（高加索人，非裔美国人，西班牙裔），他们在生活中同意参加NNTC项目。 可以假设，与HIV-1+病例的上述大脑区域相比，在上述HIV-1+病例的大脑区域中，5-HT和其代谢产物的水平及其代谢产物的水平将降低。并且5-HT和5-HIAA水平将与HIV-1+病例的相同大脑区域以及在相应的HIV-1+个体的生命期间评估的抑郁症分数中与病毒负荷负相关。我们建议在这些HIV-1+个体的大脑区域中检查5-HT和5-HIAA水平，这些人在生命中进行了评估，在死亡前至少六个月，使用Beck抑郁量库存（BDI）进行抑郁症，并研究中央5-HTactivity和病毒载荷之间在同一艾滋病毒和未经治疗的HIV-1+个体中与HART治疗的人之间的关系。该探索性R-21项目的发现将描述HIV-1相对于5-HT活动的特定区域脆弱性。此外，数据将为我们提供RO1应用的机会，以研究HIV-1感染病例的不同大脑区域中的5- ht受体和5-HT转运蛋白的其他参数，并探索新的相关治疗策略的可能性。公共卫生相关性：该R-21提案探讨了HIV-1感染对艾滋病毒/艾滋病病例后不同地区的中枢神经系统血清素能活性的影响。有人提出，HIV-1诱导涉及血清素能活性的大脑各个区域的神经变性。我们将确定5-HT及其代谢产物的5-HIAA的水平，在脑干raphe核中，在该核中，在其中含有血清素能神经元的细胞体，并合成5-HT，以及在其他各个区域中，高度支配了血清素能预测，并参与了许多生理和行为功能。这项研究的发现将大大增强我们对HIV-1诱导的中枢性血清素能缺陷的影响的理解，这可能有助于设计有助于改变中枢性血清素能活性的干预策略，并改善HIV-1感染个体的生活质量。