VILIP-1 and AD with Psychosis

VILIP-1 和 AD 伴精神病

• 批准号: 8456291
• 负责人: Caitlin M Kirkwood
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456291
• 关键词: Affect; Alzheimer' s Disease; American; Americas; Amyloid; Amyloid beta-Protein; Attenuated; Binding; Binding Proteins; Biological Markers; Calcium; Caregivers; Cerebral cortex; Cessation of life; Chemicals; Clathrin; Data; Delusions; Dendritic Spines; Deposition; Development; Disease; Down-Regulation; EF Hand Motifs; Endocytosis; Excitatory Synapse; Figs - dietary; Fluorescence Microscopy; Fostering; Freezing; Future; Genes; Goals; Gray unit of radiation dose; Hallucinations; Health; Human; Impaired cognition; In Vitro; Individual; Investigation; Lead; Literature; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurobiology; Neurons; Pathology; Patients; Peripheral; Personal Satisfaction; Phenotype; Play; Prefrontal Cortex; Process; Proteins; Psychotic Disorders; RNA Interference; Relative (related person); Research; Research Personnel; Risk; Rodent Model; Role; Societies; Solid; Structure; Synapses; System; Testing; Tg2576; Therapeutic; Tissues; Toxic effect; Training; Transgenic Mice; United States; VSNL1 gene; Vertebral column; Western Blotting; cohort; density; experience; functional decline; genome wide association study; gray matter; hippocalcin; human tissue; immunocytochemistry; improved; in vitro Model; in vivo; member; mouse model; neocortical; neuroprotection; protein expression; receptor; research study; response; sensor; translational study

DESCRIPTION (provided by applicant): This application proposes an integrated set of research aims and training experiences with the goal of fostering the applicant's development into an independent researcher conducting translational studies of disease modifying mechanisms in neurodegeneration. Alzheimer disease with psychosis (AD+P) occurs in approximately half of all Alzheimer disease subjects and identifies a phenotype with accelerated cognitive and functional decline in comparison to AD subjects without psychosis (AD-P). Underlying the rapid cognitive decline of AD+P is increased neocortical synaptic pathology. A growing pool of evidence implicates soluble amyloid beta (A¿) oligomers as a primary toxic agent in AD, which initiates NMDA receptor dependent mechanisms of LTD (LTDNMDAR), resulting in synapse loss. Our lab has been conducting investigations of how this process may be modified in AD+P. Recent genome wide association study of AD+P identified an association of the VSNL1 gene with AD+P. VSNL1 encodes VILIP-1, a neuronal calcium sensor (NCS) in a subfamily of closely related proteins which are necessary for LTDNMDAR. VILIP-1 has also recently been identified as a peripheral biomarker of AD. Preliminary data indicates that VILIP-1 is reduced in the cortex in a mouse model of A¿ overproduction, and in post-mortem dorsolateral prefrontal cortex tissue from AD-P subjects compared to control subjects. The decrease in VILIP-1 was greater in AD-P than in AD+P subjects (control>AD+P>AD-P). These findings have led me to hypothesize that VILIP-1 protein expression is decreased in response to A¿, reducing vulnerability to soluble A¿-induced synapse loss by counteracting A¿ initiated LTDNMDAR, and this neuroprotective effect is attenuated in AD+P. I will test this hypothesis in a set of highly translational aims combining human post-mortem, rodent model, and primary neuronal culture studies. The planned studies will provide me training in human tissue studies of AD, advanced quantitative fluorescence microscopy, experimental manipulation of primary neuronal cultures, and RNAi. Successful completion of the proposed Aims will indicate the direction of VILIP-1 expression alteration in the presence of A¿; will reveal whether altered expression of VILIP-1 modifies the impact of A¿ on dendritic spines, and; will lead to further studies investigating of the effects of VILIP-1 on mechanisms of LTD. Ultimately, understanding the mechanisms of VILIP-1 in AD+P will direct future therapeutic strategies to improve the health and well- being of older Americans suffering from Alzheimer disease. PUBLIC HEALTH RELEVANCE: Psychosis in Alzheimer's disease (AD+P) is a highly heritable phenotype of AD that occurs in 40-60% of the estimated 5.2 million individuals with AD in the United States of America. AD+P presents with an accelerated trajectory of cognitive and functional decline, which is associated with greater neocortical synaptic pathology. Current treatments for AD+P have limited efficacy and are associated with substantial toxicity, resulting in increased risk of death. Understanding distinct causal neurobiological factors, like the role of VILIP-1 in AD+P, will lead to improved therapeutic strategies and profoundly impact patients, caregivers, and society as a whole.

描述（由申请人提供）：本申请提出了一套完整的研究目标和培训经验，目的是促进申请人发展成为一名独立的研究人员，对神经退行性疾病的疾病修饰机制进行转化研究。阿尔茨海默病伴精神病（AD+P）发生在大约一半的所有阿尔茨海默病受试者中，并且与不伴精神病的AD受试者（AD-P）相比，鉴定出具有加速的认知和功能下降的表型。AD+P的快速认知能力下降的基础是新皮质突触病理学的增加。越来越多的证据表明，可溶性淀粉样蛋白β（A？）寡聚体是AD的主要毒性因子，可启动LTD（LTDNMDAR）的NMDA受体依赖性机制，导致突触丢失。我们的实验室一直在进行研究，如何在AD+ P的这一过程可能会被修改。最近的全基因组关联研究AD+P确定了关联的VSNL 1基因与AD+ P。VSNL 1编码VILIP-1，神经元钙传感器（NCS）在一个亚家族的密切相关的蛋白质，这是必要的LTDNMDAR。VILIP-1最近也被确定为AD的外周生物标志物。初步数据表明，VILIP-1是减少在皮质中的小鼠模型的A ²生产过剩，并在死后背外侧前额叶皮质组织从AD-P的受试者相比，对照受试者。AD-P组VILIP-1的下降幅度大于AD+P组（对照组>AD+P组> AD-P组）。这些发现使我假设，VILIP-1蛋白表达减少，响应于A？，减少脆弱性可溶性A？诱导的突触损失抵消A？启动LTDNMDAR，这种神经保护作用减弱AD+ P。我将测试这一假设在一组高度翻译的目的结合人类尸检，啮齿动物模型，和原代神经元培养研究。计划中的研究将为我提供AD的人体组织研究、高级定量荧光显微镜、原代神经元培养的实验操作和RNAi方面的培训。成功完成所提出的目标将表明VILIP-1表达在A？存在下的改变方向;将揭示VILIP-1表达的改变是否改变A？对树突棘的影响;将导致进一步的研究调查VILIP-1对LTD机制的影响。最终，了解VILIP-1在AD+P中的机制将指导未来的治疗策略，以改善患有阿尔茨海默病的美国老年人的健康和福祉。 公共卫生关系：阿尔茨海默病中的精神病（AD+P）是AD的高度可遗传表型，其发生在美国估计的520万AD个体中的40-60%中。AD+P呈现认知和功能下降的加速轨迹，这与更大的新皮质突触病理学相关。目前AD+P的治疗效果有限，并伴有大量毒性，导致死亡风险增加。理解不同的因果神经生物学因素，如 VILIP-1在AD+P中的应用将导致改善治疗策略，并对患者，护理人员和整个社会产生深远的影响。