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.

项目摘要：阿尔茨海默氏病（AD）和心力衰竭（HF）是年龄依赖性疾病，导致年龄较大患者。在AD患者中还报道了明显的心脏病理和功能障碍 AD的鼠标模型。尽管进行了广泛的研究，但HF和AD之间的关系仍然在很大程度上不清楚。我们对AD中的Sigma-1受体（SIGMAR1）蛋白的分子功能感兴趣研究表明：i）AD患者的验尸样本中降低了SIGMAR1结合位点，ii） SIGMAR1的密度在AD早期降低，III）Sigmar1中的多态性与改变有关 AD风险。我们发现sigmar1在体内绝对表达，而sigmar1全局敲除鼠标心脏显示的线粒体呼吸受损，表明Sigmar1在细胞中的潜在功能代谢。在父母的建议中，我们想检验中心假设，即SIGMAR1依赖性激活新陈代谢可免受代谢应激诱导的心脏功能障碍和病理重塑的保护。为了确定SIGMAR1在AD发病机理中的分子功能，我们将使用AppSwe/ps1 double 表达嵌合小鼠/人淀粉样蛋白前体蛋白（MO/HUAPP695SWE）的转基因小鼠和A 突变的人类老年蛋白1（PS1-DE9）。 Appswe/PS1鼠标模型具有广告病理学，包括 Aβ和磷酸化的tau蛋白的积累以及认知障碍，也发展心肌细胞收缩功能障碍。在这里，我们将测试持续Sigmar1的中心假设 APSSWE/PS1MOUSE AD模型中的表达将减少Aβ的积累和细胞损伤通过激活线粒体能量代谢，大脑和心脏。在当前的阿尔茨海默氏症提案，我们将确定SIGMAR1在Aβ积累，认知功能障碍和心脏方面的作用 APSSWE/PS1鼠标AD的功能障碍（AIM 1），并确定持续的SIGMAR1是否依赖线粒体能量代谢和功能的恢复救援AD发病机理和心脏功能障碍 APP/PS1鼠标（AIM 2）。我们将在结合中使用集成的分子，遗传和功能方法用一般修饰的小鼠确定直接参与并定义分子机制 SIGMAR1在AD发病机理中的作用。这个提议的项目将确定保护的新型热目标针对APPSWE/PS1诱导的代谢改变，线粒体功能障碍，细胞损伤和逆境病理重塑。