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，阿尔茨海默氏病（AD）会影响超过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和痴呆症中起着关键作用。 因此，改善脉管系统病理学的任何策略在治疗上都是极具吸引力的。在 父母提议，我们提出腺苷酸核酸酯（ADSUCC）是脑内源性亲血管生成因子。在 当前的提案，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 促进与年龄相关的大脑变化并引起功能缺陷，包括类似AD 病理。父母奖的当前第二预算年度收集的数据强烈支持我们 新型ADSUCC促血管生成机制。我们发现，在大脑低的大脑下，ADSUCC显着增加 能量条件并促进脑血管生成以补偿这些条件。但是，我们 出乎意料地发现，ADSUCC的产生在老年小鼠中下降，表明ADSUCC血管生成 机制功能障碍可能导致与年龄相关的脑脉管系统的改变，从而有助于认知 障碍和痴呆症，包括广告。但是，这种初步观察需要进一步的系统 验证，合理化我们的行政补充请求。我们的中心假设将通过 遵循父母奖的现有特定目的的子iams： 1。确定在低能量条件下老年小鼠的ADSUCC产生是否降低 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生产降低是否导致AD样病理 履行这些子iams将把我们的新型ADSUCC介导的脑血管生成的机制与 阿尔茨海默氏病的发展及其对认知障碍和痴呆症的贡献。这很重要 因为如果成功，它将验证一种新的机制，并概述这些新的潜在治疗靶标 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 项目具有创新性，因为它解决了先前未认可的大脑信号传导机制 血管生成并建立了与年龄有关的脉管系统障碍和痴呆的新型机制， 包括广告。拟议的工作属于父母奖的范围，因为这两个项目都解决了 在相同的低能量下，同一新型ADSUCC机制对脑血管生成的贡献 条件，而行政补充剂则将母公司项目扩展到包括其他老年人 小鼠的种群。

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.