The Role of Presenilins in HIV Associated Dementia

早老素在 HIV 相关痴呆中的作用

基本信息

批准号：
7914330
负责人：
SUMAN JAYADEV
金额：
$ 16.71万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914330
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Age-associated memory impairment Aging Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Autopsy Award Binding Biological Assay Brain Brain Injuries C-terminal Capsid Proteins Cell physiology Cells Chronic Cleaved cell Co-Immunoprecipitations Code Comorbidity Complex Confocal Microscopy Consequences of HIV Coupled Data Dementia Development Disease Environment ErbB4 gene Exposure to Family health status Genes Glycoproteins Growth Factor HIV HIV Envelope Protein gp120 HIV Infections Healthcare Systems Highly Active Antiretroviral Therapy Histopathology Human Immune Immunohistochemistry Impaired cognition In Vitro Individual Inflammation Inflammatory Inflammatory Response Knockout Mice Lead Long-Term Survivors Measures Mediating Membrane Mentors Microglia Morbidity - disease rate Mutation N-terminal NGFR Protein Neuraxis Neurodegenerative Disorders Nuclear Pathway interactions Patients Peptide Hydrolases Prevalence Process Protein Binding Protein C Proteins Proteomics Reporter Reporting Research Research Personnel Rest Role Scientist Signal Pathway Signal Transduction Signaling Protein Stimulus Techniques Therapeutic Training Work amyloid peptide brain tissue career development cell type cytokine familial Alzheimer disease human APH-1 protein human PEN-2 protein improved interdisciplinary approach knock-down mortality neuroinflammation neurotoxic nicastrin protein notch protein novel presenilin presenilin-1 presenilin-2 programs protein complex protein expression protein protein interaction response secretase small hairpin RNA symposium tandem mass spectrometry tool transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): HIV associated dementia (HAD) is a significant and potentially treatable cause of cognitive decline. Despite improved AIDS mortality rates with the advent of highly active anti-retroviral therapy (HAART), the prevalence of HAD is increasing. Neuropathological studies of brain tissue from patients with HAD and other neurodegenerative diseases such as Alzheimer's disease (AD), reveal evidence of prominent neuroinflammatory changes including activation of microglia, the resident brain immune cells. Mutations in the genes coding for the presenilin proteins (PS), presenilin 1 (PS1) and presenilin 2 (PS2) cause familial AD, and thus PS are a natural focus of study in neurodegenerative disease. PS are the catalytic component of the y-secretase complex, a membrane protease that processes amyloid peptide protein to form amyloid beta peptide, found in AD plaques. The PS y-secretase complex also cleaves numerous substrates such as ErbB4, Notch, p75 that have been implicated in inflammatory processes. Previous work suggests a role for PS in central nervous system inflammation and our preliminary data demonstrate that PS2 protein is increased in HAD brain as well as in microglia stimulated by the HIV coat protein, gp120. In this K08 career development proposal, we hypothesize that PS are integral to the neuroinflammatory processes in HAD. During the award period the investigator will study the effects of pharmacological y-secretase inhibition and shRNA knock down of PS in microglia activated by the HIV coat protein, gp120. Primary microglia from PS2 knockout mice will be assayed for gp120 induced activation. Using immunohistochemistry we will investigate cell type and sub-cellular expression in HAD brain of two Y-secretase substrates implicated in the microglia inflammatory response, ErbB4 and p75NTR. We will determine if the known y-secretase components assemble in microglia using co-immunoprecipitation and measure microglia y-secretase activity in response to inflammatory stimuli. PS are known to mediate cellular functions independent of the y-secretase complex, and therefore we will employ proteomic techniques to identify novel PS binding partners in quiescent and gp120 stimulated microglia. A multidisciplinary approach including mentored bench research, didactics, seminars and professional conferences will provide the necessary training environment to promote the development of this young investigator into an independent clinician-scientist. HAD is a costly burden to individuals, families and the health care system. This proposal will contribute to the fundamental understanding of mechanisms in HIV induced neuroinflammation that will potentially lead to more effective therapeutics in the treatment of HAD.

描述（由申请人提供）：HIV 相关痴呆 (HAD) 是认知能力下降的一个重要且可能可治疗的原因。尽管随着高效抗逆转录病毒疗法 (HAART) 的出现，艾滋病死亡率有所下降，但 HAD 的患病率仍在增加。对 HAD 和其他神经退行性疾病（例如阿尔茨海默氏病 (AD)）患者脑组织的神经病理学研究揭示了显着的神经炎症变化的证据，包括小胶质细胞（大脑常驻免疫细胞）的激活。编码早老素蛋白 (PS)、早老素 1 (PS1) 和早老素 2 (PS2) 的基因突变会导致家族性 AD，因此 PS 自然成为神经退行性疾病研究的焦点。 PS 是 γ-分泌酶复合物的催化成分，γ-分泌酶复合物是一种膜蛋白酶，可将淀粉样肽蛋白加工成淀粉样β肽，存在于 AD 斑块中。 PS y-分泌酶复合物还裂解许多与炎症过程有关的底物，例如 ErbB4、Notch、p75。先前的工作表明 PS 在中枢神经系统炎症中发挥作用，我们的初步数据表明，PS2 蛋白在 HAD 大脑以及受 HIV 外壳蛋白 gp120 刺激的小胶质细胞中增加。在这个 K08 职业发展提案中，我们假设 PS 是 HAD 神经炎症过程中不可或缺的一部分。在获奖期间，研究人员将研究药理学 y 分泌酶抑制和 shRNA 敲低 HIV 外壳蛋白 gp120 激活的小胶质细胞中 PS 的影响。将检测 PS2 敲除小鼠的原代小胶质细胞的 gp120 诱导激活。我们将使用免疫组织化学研究 HAD 脑中两种与小胶质细胞炎症反应有关的 Y 分泌酶底物 ErbB4 和 p75NTR 的细胞类型和亚细胞表达。我们将使用免疫共沉淀确定已知的 y-分泌酶成分是否在小胶质细胞中组装，并测量小胶质细胞 y-分泌酶对炎症刺激的反应活性。已知 PS 能够独立于 y-分泌酶复合物介导细胞功能，因此我们将采用蛋白质组学技术来鉴定静止和 gp120 刺激的小胶质细胞中新的 PS 结合伴侣。包括指导实验研究、教学、研讨会和专业会议在内的多学科方法将为促进这位年轻研究者发展成为独立的临床医生科学家提供必要的培训环境。 HAD 对个人、家庭和医疗保健系统来说是一个昂贵的负担。该提案将有助于从根本上理解 HIV 诱发的神经炎症机制，从而有可能开发出更有效的 HAD 治疗方法。