Phospholipase D1 Mediated Early Events Affecting Synaptic Dysfunction in Alzheimer's Disease and Related Dementia

磷脂酶 D1 介导影响阿尔茨海默病和相关痴呆症突触功能障碍的早期事件

基本信息

批准号：
10599363
负责人：
BALAJI KRISHNAN
金额：
$ 39.5万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599363
关键词：
3xTg-AD mouse AD transgenic mice Address Affect Age Age of Onset Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid Attention Automobile Driving Autopsy Behavioral Biochemical Brain Cause of Death Clinical Trials Co-Immunoprecipitations Cognitive deficits Creativeness Data Dementia Dendritic Spines Development Disease Electrophysiology (science)Etiology Event Fluorescence Fostering Frontotemporal Dementia Functional disorder Future Goals Health Hippocampus Human Impaired cognition Knowledge Long-Term Potentiation Mechanics Mediating Memory Memory impairment Mission Molecular Mus Nerve Degeneration Neurons PRKCA gene Patients Phospholipase D Protein Isoforms Proteins Proteomics Public Health Publishing Quality of life Reporting Research Role Signal Transduction Sirolimus Synapses Synaptosomes Tauopathies Temporal Lobe Testing Therapeutic Therapeutic Intervention Transgenic Mice United States National Institutes of Health Up-Regulation Western Blotting abeta oligomer adeno-associated viral vector brain tissue cofilin effective therapy halopemide imaging study improved inhibitor insight mouse model neuropathology novel overexpression phospholipase D1 pre-clinical preclinical study prevent recruit small hairpin RNA small molecular inhibitor small molecule small molecule inhibitor synaptic function tau Proteins therapeutically effective vector

项目摘要

PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer’s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Attention has shifted towards under- standing early synaptic events in AD and related dementia (ADRD), resulting in memory deficits. However, the mechanism recruited and leading to synapse dysfunction associated memory deficits remains elusive thus im- peding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that inducible phospholipase D (PLD1) overexpression and the resulting aberrant signaling contributes to the progressive detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: (I) testing how elevated synaptic PLD1 levels/signaling contributes to synaptic dysfunction and memory deficits in ADRD; (II) evaluating the functional contribution of elevated PLD1 in preclinical mouse models and studying partners contributing to ADRD-like synaptic dysfunction and memory deficits. The present project is highly significant because the proposed studies will establish elevated PLD1 and the associated signaling part- ners as key players in promoting vulnerability causing progressive synaptic dysfunction and underlying cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using well-tolerated small molecule PLD1 inhibitor in preventing memory deficits asso- ciated with ADRD progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by elevated PLD1 and interacting signaling partners in contributing to synaptic vulnera- bility.

项目摘要/摘要尽管过去二十年的研究取得了重大进展，但阿尔茨海默氏病（AD）仍然是第六个无法预防，治愈甚至放缓的主要死亡原因。注意已转向不足在AD和相关痴呆症（ADRD）中站立的早期突触事件，导致记忆定义。但是，招募的机制并导致突触功能障碍相关记忆的定义仍然难以捉摸踩踏成功的热干预。在我们当前的知识中弥合这一关键差距是这个目标提议。我们提出了令人信服的初步结果，以支持我们的假设，即诱导磷脂酶D （PLD1）过表达和由此产生的异常信号传导有助于对渐进的有害影响突触和随后的认知缺陷。我们将通过追求以下特定的特定来检验中心假设目的：（i）测试合成PLD1级别/信号的升高如何有助于突触功能障碍和内存在ADRD中定义；（ii）评估临床前小鼠模型中升高PLD1的功能贡献和研究伴侣为ADRD样突触功能障碍和记忆定义。目前的项目是高度重要作为促进脆弱性引起渐进性突触功能障碍和潜在认知能力的关键参与者缺陷。成功完成目标将提供有关所涉及的分子机制和使用耐受良好的小分子PLD1抑制剂的治疗可能性可防止记忆定义与Adrd进展。拟议的项目将提高我们对突触的科学理解功能障碍是由PLD1升高和相互作用的信号伴侣介导的，从而导致突触能力。