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 这项研究的目的是评估一般的口服递送乳杆菌的影响 修改以表达阿尔茨海默氏病（AD）的血管紧张素（1-7）（LP-A）。 AIM 1将检验以下假设 病理发作时的LP-A处理将显着减慢或延迟PTAU和Aβ的积累，标记物 TGF344-AD大鼠的炎症，去甲肾上腺素能的损失以及海马突触功能障碍 取决于MAS受体的激活。 AIM 2将检验LP-A处理改善的假设 在海马依赖性行为测定中的表现，并降低TGF344-AD大鼠中的动画 取决于MAS受体的激活。预期的影响：迄今为止，可预防的经过验证的治疗方法 缺乏年龄和广告介导的认知下降，因此对潜在有效干预措施的研究是 迫切需要。这项研究具有生成概念数据证明的巨大潜力 提供干预可以改善或阻止突触电路和认知功能中的防御能力。工作是 意义重大，因为它解决了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交付的概念方法 益生菌形式的治疗化合物以及为将来翻译奠定基础的研究设计 对于人类，最终有助于解决与AD相关认知能力下降的大规模健康燃烧。