ANG1-7 as an intervention for Alzheimer's Disease.

ANG1-7 作为阿尔茨海默病的干预措施。

• 批准号: 10592577
• 负责人: Thomas W Buford
• 金额: $ 19.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592577
• 关键词: ANGPT1 gene; Address; Adrenergic Agents; Adrenergic Receptor; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amino Acids; Amyloid beta-Protein; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Anxiety; Area; Axon; Behavior; Behavioral Assay; Blood Pressure; Brain; Centers for Disease Control and Prevention (U.S.); Clinical; Cognition; Data; Disease Progression; Dose; Drosophila genus; Elderly; Encephalitis; Engineered Probiotics; Fluid Balance; Functional disorder; Future; G-Protein-Coupled Receptors; Genetic Engineering; Gliosis; Health; Hippocampus; Histology; Hormonal; Human; Impaired cognition; Inbred BN Rats; Inflammation; Inflammatory; Interruption; Intervention; Intraperitoneal Injections; Intraventricular Infusion; Investigation; Lactobacillus; Learning; Life; Medial; Mediating; Memory; Messenger RNA; Methods; Modeling; Nerve Degeneration; Neuroglia; Neurons; Oral; Osmosis; Pathology; Peptides; Peptidyl-Dipeptidase A; Perforant Pathway; Performance; Peripheral; Prefrontal Cortex; Probiotics; Public Health; Quality of life; Rattus; Recombinant Proteins; Regimen; Renin-Angiotensin System; Reporting; Research; Research Design; Rodent; Signal Transduction; Signaling Molecule; Subcutaneous Injections; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Thinking; Transgenic Organisms; United States National Institutes of Health; Work; aged; aging population; brain health; cognitive function; cognitive performance; efficacious intervention; experience; granule cell; gut-brain axis; high risk; improved; inflammatory marker; innovation; locus ceruleus structure; mutant; neural circuit; neuronal excitability; noradrenergic; novel; novel therapeutic intervention; pre-clinical; prevent; public health relevance; receptor; receptor function; sex; translation to humans; translational potential

PROJECT SUMMARY The objective of this study is to evaluate the impact of orally delivering Lactobacillus paracasei genetically modified to express Angiotensin (1-7) (LP-A) on Alzheimer’s Disease (AD). Aim 1 will test the hypothesis that LP-A treatment at the onset of pathology will significantly slow or delay accumulation of pTau and Aβ, markers of inflammation, loss of noradrenergic axons, and hippocampal synaptic dysfunction in TgF344-AD rats that is dependent upon activation of Mas receptors. Aim 2 will test the hypothesis that LP-A treatment improves performance in hippocampus-dependent behavioral assays and decreases anxiety in TgF344-AD rats that is dependent upon activation of Mas receptors. ANTICIPATED IMPACT: To date, proven treatments for preventing age- and AD mediated cognitive decline are lacking, thus research on potentially efficacious interventions is desperately needed. This study holds tremendous potential for generating proof of concept data that an orally- provided intervention improves or prevents deficits in synaptic circuit and cognitive function. The work is significant because it addresses several clinical and public health problems deemed critical by the NIH. Innovations in the project include the conceptual approach using genetic engineering techniques to deliver therapeutic compounds in probiotic form, and the study design which lays the groundwork for future translation to humans to ultimately help address the massive health burden of AD related cognitive decline.

项目摘要 本研究的目的是评估口服副干酪乳杆菌对遗传的影响， 经修饰以表达阿尔茨海默病（AD）的血管紧张素（1-7）（LP-A）。目标1将检验以下假设： 病理学开始时的LP-A治疗将显著减缓或延迟pTau和Aβ标志物的积累 TgF 344-AD大鼠的炎症、去甲肾上腺素能轴突丢失和海马突触功能障碍， 依赖于Mas受体的激活。目的2将检验LP-A治疗改善 在海马依赖性行为测定中的表现并降低TgF 344-AD大鼠的焦虑，即 依赖于Mas受体的激活。预期影响：迄今为止，已证实的预防 缺乏年龄和AD介导的认知功能下降，因此对潜在有效干预措施的研究 迫切需要的。这项研究具有巨大的潜力，产生概念数据的证明，一个口头- 提供的干预改善或预防突触回路和认知功能的缺陷。这项工作是 重要的是，它解决了NIH认为至关重要的几个临床和公共卫生问题。 该项目的创新包括使用基因工程技术的概念方法， 益生菌形式的治疗化合物，以及为未来翻译奠定基础的研究设计 最终帮助解决AD相关认知能力下降的巨大健康负担。