Proof-of-Concept and Mechanistic Studies to Repurpose Erectile Dysfunction Drugs for Elderly Females

重新利用老年女性勃起功能障碍药物的概念验证和机制研究

• 批准号: 10714784
• 负责人: Se-min Kim
• 金额: $ 42.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714784
• 关键词: 3xTg-AD mouse; Administrative Supplement; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Biological; Brain; Brain region; CREB1 gene; Cell Nucleus; Cells; Cialis; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Early Onset Alzheimer Disease; Elderly; Enzymes; Erectile dysfunction; Female; Funding; Genes; Goals; Grant; Health Hazards; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Investigation; Knock-out; Maps; Measures; Mediating; Memory; Mus; Nitric Oxide; Osteoporosis; Parents; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Postmenopausal Osteoporosis; Property; Proteins; Public Health; Research; Role; Sampling; Signal Transduction; Spatial Distribution; Testing; Transcript; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Variant; Viagra; Woman; aged; bone; cohort; drug action; drug repurposing; effective therapy; human data; improved; inhibitor; loss of function; male; memory recognition; men; morris water maze; neurobehavioral test; neuropathology; novel; object recognition; overexpression; phosphodiesterase 11a; phosphoric diester hydrolase; preclinical study; prevent; pulmonary arterial hypertension; sildenafil; spatial memory; tadalafil; tau-1; transcription factor; vardenafil

PROJECT SUMMARY Alzheimer’s disease (AD) is a public health crisis with no effective treatment1. Preclinical studies using a group of drugs—commonly termed "PDE5A inhibitors”, which include tadalafil, vardenafil and sildenafil—have shown that the suppression of the enzyme phosphodiesterase 5A (PDE5A) can improve memory in mice prone to AD. This begs the question whether these drugs, currently in clinical use for erectile dysfunction and pulmonary artery hypertension, can be repurposed for AD patients. Such an approach would merit a thorough investigation into the mechanism of action of PDE5A inhibitors on brain function. Complexities however arise from the fact that the structurally–related enzyme PDE11A is also expressed abundantly in various AD– vulnerable brain regions, such as the cortex and hippocampus, and that tadalafil potently inhibits PDE11A, albeit with a 7–fold higher IC50 compared with PDE5A. It is therefore imperative that we (a) tease apart the relative effects of inhibiting PDE5A and PDE11A on cognitive loss, and (b) determine whether PDE11A is itself an actionable target. Towards these goals, we will first map the expression of Pde5a and Pde11a transcripts using qPCR, RNAscope and immunohistochemistry in various brain regions and sub–regions of aged mice and 3xTg mice (Specific Aim 1). We will then inject CRISPR constructs for Pde5a and Pde11a stereotactically into the hippocampus of 3xTg mice to determine whether PDE5A and/or PDE11A inhibition prevent cognitive decline, measured by the Novel Object Recognition and Morris Water Maze tests, and amyloidogenic protein accumulation (Specific Aim 2). Consistent with the goals of the Administrative Supplement under PA–20–272, NOT–AG–22–025, this 1–year project will yield preliminary data towards a new R01 application to fully study a role for PDE5A and PDE11A in brain function.

项目概要 阿尔茨海默病 (AD) 是一种公共卫生危机，目前尚无有效的治疗方法1。 一组药物（通常称为“PDE5A 抑制剂”，包括他达拉非、伐地那非和西地那非）具有 研究表明，抑制磷酸二酯酶 5A (PDE5A) 可以改善小鼠的记忆力 这就引出了一个问题：这些药物目前在临床上是否用于治疗勃起功能障碍？ 肺动脉高压，可以重新用于 AD 患者，这种方法值得彻底研究。 然而，PDE5A 抑制剂对大脑功能作用机制的研究却出现了复杂性。 事实上，结构相关的酶 PDE11A 在各种 AD 中也大量表达—— 脆弱的大脑区域，例如皮质和海马体，并且他达拉非有效抑制 PDE11A， 与 PDE5A 相比，IC50 可能高 7 倍。因此，我们必须 (a) 梳理出这一点。 抑制 PDE5A 和 PDE11A 对认知丧失的相对影响，以及 (b) 确定 PDE11A 是否是其本身 为了实现这些目标，我们将首先绘制 Pde5a 和 Pde11a 转录本的表达图谱。 使用 qPCR、RNAscope 和免疫组织化学检测老年小鼠的各个大脑区域和亚区域 和 3xTg 小鼠（具体目标 1），然后我们将立体定向注射 Pde5a 和 Pde11a 的 CRISPR 构建体。 进入 3xTg 小鼠的海马以确定 PDE5A 和/或 PDE11A 抑制是否会妨碍认知 通过新物体识别和莫里斯水迷宫测试测量，以及淀粉样蛋白的下降 积累（具体目标 2）与 PA-20-272 下的行政补充文件的目标一致， NOT-AG-22-025，这个为期一年的项目将为新的 R01 应用提供初步数据，以全面研究 PDE5A 和 PDE11A 在大脑功能中的作用。