Molecular signaling linking Alzheimer's disease and heart failure

阿尔茨海默病和心力衰竭之间的分子信号传导

基本信息

批准号：
10287798
负责人：
Md. Shenuarin Bhuiyan
金额：
$ 36.5万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287798
关键词：
Accounting Adrenergic Agents Age-Years Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Architecture Autopsy Binding Sites Biochemical Brain Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cessation of life Clinical Research Dementia Deposition Development Disease Energy Metabolism Etiology Exhibits Functional disorder Generations Genetic Genetic Polymorphism Goals Heart Heart failure Homeostasis Human Human Amyloid Precursor Protein Impaired cognition Impairment In Vitro Knockout Mice Link Mediating Memory Loss Metabolic Metabolic dysfunction Metabolic stress Metabolism Mitochondria Modeling Molecular Molecular Genetics Molecular Target Morphology Mus Mutation Myocardial Myocardial dysfunction Myocardium Neurodegenerative Disorders Parents Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Physiological Plant Roots Presenile Alzheimer Dementia Reactive Oxygen Species Receptor Activation Reporting Research Respiration Risk Role Sampling Senile Plaques Signal Transduction Stress Structure Testing Transgenic Mice Transgenic Organisms abeta accumulation age related cell injury cognitive function density extracellular genetic regulatory protein in vivo interest lipid metabolism loss of function mitochondrial dysfunction mitochondrial metabolism mouse model mutant nervous system disorder new therapeutic target novel older patient overexpression presenilin-1 pressure prevent receptor receptor expression receptor function restoration sigma-1 receptor tau Proteins tau-1 therapeutic target

项目摘要

Project Summary: Alzheimer’s disease (AD) and heart failure (HF) are age-dependent diseases causing a substantial death in older patients. Pronounced cardiac pathology and dysfunction has also been reported in AD patients and different mouse model of AD. Despite extensive studies, the relationship between HF and AD remains largely unclear. We became interested in uncovering the molecular function of Sigma-1 receptor (Sigmar1) proteins in AD as studies showed that: i) Sigmar1 binding sites are reduced in postmortem samples from patients with AD, ii) the density of Sigmar1 is reduced in early AD, and iii) polymorphisms in Sigmar1 have been associated with altered risk for AD. We found that Sigmar1 is abundantly expressed in the body and Sigmar1 global knockout mouse heart showed impaired mitochondrial respiration suggesting a potential function of Sigmar1 in cellular metabolism. In the parent proposal, we wanted to test the central hypothesis that Sigmar1-dependent activation of metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling. To determine, the molecular function of Sigmar1 in AD pathogenesis, we will use the APPswe/PS1 double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9). The APPswe/PS1 mouse model having AD pathology, including accumulation of Aβ and phosphorylated tau proteins, as well as cognitive impairment and also develop cardiomyocyte contractile dysfunction. Here, we will test the central hypothesis that sustained Sigmar1 expression in the APPswe/PS1mouse model of AD will decrease the Aβ accumulation and cellular injury in the brain and heart through activation of mitochondrial energy metabolism. In this present Alzheimer’s supplement proposal, we will determine the role of Sigmar1 in Aβ accumulation, cognitive dysfunction and cardiac dysfunction in APPswe/PS1 mouse model of AD (Aim 1) and determine if sustained Sigmar1 dependent restoration of mitochondrial energy metabolism and function rescue AD pathogenesis and cardiac dysfunction APP/PS1 mouse (Aim 2). We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement and define the molecular mechanisms of Sigmar1’s role in AD pathogenesis. This proposed project will identify a novel therapeutic target in protecting against APPswe/PS1-induced metabolic alterations, mitochondrial dysfunction, cellular injury, and adverse pathological remodeling.

项目概要：阿尔茨海默病 (AD) 和心力衰竭 (HF) 是导致老年人大量死亡的年龄依赖性疾病 AD 患者和其他患者也有明显的心脏病理学和功能障碍的报道。 AD 小鼠模型尽管进行了大量研究，但 HF 和 AD 之间的关系仍不清楚。我们对揭示 Sigma-1 受体 (Sigmar1) 蛋白在 AD 中的分子功能产生了兴趣：研究表明：i) AD 患者死后样本中 Sigmar1 结合位点减少，ii) Sigmar1 的密度在 AD 早期降低，并且 iii) Sigmar1 的多态性与改变有关我们发现 Sigmar1 在体内大量表达，并且 Sigmar1 全基因敲除小鼠。心脏显示线粒体呼吸受损，表明 Sigmar1 在细胞中的潜在功能在父提案中，我们想要测试 Sigmar1 依赖性激活的中心假设。代谢的调节可防止代谢应激引起的心脏功能障碍和病理重塑。为了确定 Sigmar1 在 AD 发病机制中的分子功能，我们将使用 APPswe/PS1 双转基因小鼠表达嵌合小鼠/人淀粉样前体蛋白（Mo/HuAPP695swe）和突变型人早老素 1 (PS1-dE9) 具有 AD 病理学的 APPswe/PS1 小鼠模型，包括 Aβ 和磷酸化 tau 蛋白的积累以及认知障碍也会发展在这里，我们将测试维持 Sigmar1 的中心假设。 AD 的 APPswe/PS1 小鼠模型中的表达将减少 Aβ 积累和细胞损伤通过激活线粒体能量代谢来调节大脑和心脏。提案中，我们将确定 Sigmar1 在 Aβ 积累、认知功能障碍和心脏功能中的作用 APPswe/PS1 AD 小鼠模型中的功能障碍（目标 1）并确定是否持续 Sigmar1 依赖性恢复线粒体能量代谢和功能挽救AD发病机制和心功能障碍 APP/PS1 小鼠（目标 2）我们将结合使用综合分子、遗传和功能方法。与转基因小鼠一起确定直接参与并定义分子机制 Sigmar1 在 AD 发病机制中的作用该拟议项目将确定一个新的保护靶点。对抗 APPswe/PS1 诱导的代谢改变、线粒体功能障碍、细胞损伤和不良反应病理性重塑。