Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain

腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证

• 批准号: 10711027
• 负责人: Mikhail Y Golovko
• 金额: $ 32.38万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711027
• 关键词: Ablation; Address; Administrative Supplement; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer like pathology; Alzheimer' s Disease; American; Angiogenic Factor; Animals; Award; Behavior; Behavioral; Biology; Blood Vessels; Brain; Budgets; Cells; Cerebrovascular Circulation; Cerebrovascular system; Clinical; Comb animal structure; Compensation; Data; Dementia; Development; Disease; Elderly; Exposure to; Functional disorder; Funding; Hypoxia; Image; Impaired cognition; Impairment; Injections; Knockout Mice; Laboratories; Link; Mediating; Methods; Modeling; Mus; Neurologic Deficit; Neurons; Outcome; Parents; Pathologic; Pathology; Play; Population; Production; Proteins; Rationalization; Regulation; Role; Sample Size; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Therapeutic; Validation; Wild Type Mouse; Work; age related; aged; angiogenesis; expectation; experimental study; human old age (65+); in vivo; innovation; insight; middle age; multiphoton imaging; novel; parent grant; parent project; response; therapeutic target

Alzheimer's disease (AD) is estimated to affect over 5 million Americans. There is growing evidence showing that vascular pathologies and dysfunction play a critical role in cognitive impairment, clinical AD, and dementia. Therefore, any strategy to ameliorate vasculature pathology is extremely attractive therapeutically. In the parent proposal, we proposed that adenylosuccinate (AdSucc) is a brain endogenous pro-angiogenic factor. In the current proposal, we hypothesize that AdSucc-mediated brain angiogenesis declines with age, thus contributing to age-related changes of the cerebrovasculature and causing functional deficits, including AD-like pathology. Data collected during the current second budget year of the parent award strongly support our novel AdSucc pro-angiogenic mechanism. We found that AdSucc is significantly increased under brain low energy conditions and promotes brain angiogenesis to compensate for these conditions. However, we unexpectedly discovered that AdSucc production declines in aged mice, indicating that AdSucc angiogenic mechanism dysfunction might contribute to age-related alterations in cerebral vasculature and thus cognitive impairment and dementia, including AD. However, this preliminary observation needs further systematic validation, rationalizing our administrative supplement request. Our central hypothesis will be tested via the following sub-aims of the existing specific aims of the parent award: 1. Determine if AdSucc production is decreased in aged mice upon low energy conditions 2. Determine if angiogenic response to AdSucc treatment is decreased in aged mice 3. Determine if decreased AdSucc production results in AD-like pathology Fulfilling these sub-aims will link our novel mechanism for AdSucc-mediated brain angiogenesis to the development of Alzheimer's disease and its contribution to cognitive impairment and dementia. It is significant because if successful, it will validate a novel mechanism and outline new potential therapeutic targets for these pathologies based on the novel AdSucc-mediated brain angiogenesis proposed in the parent award. The project is innovative because it addresses a previously unrecognized signaling mechanism for brain angiogenesis and establishes a novel mechanism for age-related vasculature impairments and dementia, including AD. The proposed work is within the scope of the parent award as both projects address the contribution of the same novel AdSucc mechanism to brain angiogenesis under the same low energy conditions, while the administrative supplement extends the parent project to include additional elderly populations of mice.

据估计，阿尔茨海默病 (AD) 影响着超过 500 万美国人。越来越多的证据表明 血管病理和功能障碍在认知障碍、临床 AD 和痴呆中发挥着关键作用。 因此，任何改善脉管系统病理学的策略在治疗上都极具吸引力。在 在家长提案中，我们提出腺苷琥珀酸（AdSucc）是一种脑内源性促血管生成因子。在 根据目前的提议，我们假设 AdSucc 介导的脑血管生成随着年龄的增长而下降，因此 导致与年龄相关的脑血管变化并导致功能缺陷，包括 AD 样症状 病理。在母公司奖励的当前第二个预算年度收集的数据有力地支持了我们的 新颖的 AdSucc 促血管生成机制。我们发现AdSucc在脑低下时显着增加 能量状况并促进脑血管生成以补偿这些状况。然而，我们 意外地发现老年小鼠的 AdSucc 产量下降，表明 AdSucc 具有血管生成作用 机制功能障碍可能导致与年龄相关的脑血管系统的改变，从而导致认知能力的改变 损伤和痴呆，包括 AD。然而，这一初步观察还需要进一步系统化 验证，使我们的行政补充请求合理化。我们的中心假设将通过 家长奖现有具体目标的以下子目标： 1. 确定老年小鼠在低能量条件下 AdSucc 的产生是否减少 2. 确定老年小鼠对 AdSucc 治疗的血管生成反应是否降低 3. 确定 AdSucc 产量减少是否会导致 AD 样病理 实现这些子目标将把 AdSucc 介导的脑血管生成的新机制与 阿尔茨海默病的发展及其对认知障碍和痴呆的影响。意义重大 因为如果成功，它将验证一种新机制并为这些疾病概述新的潜在治疗靶点 基于父母奖中提出的新型 AdSucc 介导的脑血管生成的病理学。这 该项目具有创新性，因为它解决了以前未被识别的大脑信号传导机制 血管生成并为与年龄相关的脉管系统损伤和痴呆建立新机制， 包括AD。拟议的工作属于母奖的范围，因为这两个项目都解决了 相同的新颖 AdSucc 机制在相同低能量下对脑血管生成的贡献 条件，而行政补充将父项目扩展到包括额外的老年人 小鼠种群。

项目成果

Exogenous oxygen is required for prostanoid induction under brain ischemia as evidence for a novel regulatory mechanism.

• DOI: 10.1016/j.jlr.2023.100452
• 发表时间: 2023-11
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Seeger, Drew R.;Schofield, Brennon;Besch, Derek;Golovko, Svetlana A.;Kotha, Peddanna;Parmer, Meredith;Solaymani-Mohammadi, Shahram;Golovko, Mikhail Y.
• 通讯作者: Golovko, Mikhail Y.