Immunotherapeutic Targeting of Corticotropin-Releasing Hormone in Alzheimer's Disease

促肾上腺皮质激素释放激素在阿尔茨海默病中的免疫治疗靶向

• 批准号: 9765429
• 负责人: Hunter Futch
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765429
• 关键词: Active Immunotherapy; Acute; Adrenal Cortex Hormones; Adrenal Glands; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Antibody Response; Attenuated; Behavioral Symptoms; Binding; Biological; Biological Models; Blood - brain barrier anatomy; Brain; Bypass; Censuses; Center for Translational Science Activities; Chronic; Chronic stress; Clinical; Clinical Trials; Corticosterone; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; DNA; Data; Dementia; Deposition; Development; Disease; Elderly; Environmental Risk Factor; Epidemic; Gene Transfer Techniques; Genetic; Goals; Hippocampus (Brain); Hormone Antagonists; Human; Hypothalamic structure; Immune Sera; Immunize; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Industrialization; Infrastructure; Intervention; Keyhole Limpet Hemocyanin; Laboratories; Link; Major Depressive Disorder; Mediating; Mediator of activation protein; Medical; Monoclonal Antibodies; Monozygotic twins; Mus; Neurodegenerative Disorders; Neuropeptides; Passive Immunotherapy; Pathologic; Pathology; Pathway interactions; Peptides; Perception; Peripheral; Phase; Pituitary Gland; Play; Population; Portal System; Post-Traumatic Stress Disorders; Prevalence; Property; Psychological Stress; Recombinant adeno-associated virus (rAAV); Reporting; Risk; Role; Signal Pathway; Stimulus; Stress; Testing; Therapeutic; Transgenic Mice; Vaccines; Wild Type Mouse; Work; acute stress; associated symptom; base; behavioral impairment; biological adaptation to stress; clinical efficacy; efficacy testing; epidemiologic data; experimental study; hormonal signals; hypothalamic pituitary axis; immunogenic; in vitro Assay; in vivo; in vivo Model; interest; macromolecule; mouse model; neuropathology; neuropsychiatry; new therapeutic target; non-genetic; novel; novel therapeutics; overexpression; peptide hormone; psychological distress; receptor; response; small molecule; stress related disorder; tau Proteins; tau mutation; tau phosphorylation; therapeutic target; tool

Project Summary/Abstract Recent clinical reports indicate that chronic psychological stress may significantly increase the risk of developing Alzheimer’s Disease (AD). A major coordinator of the stress response is corticotropin-releasing hormone (CRH), a neuropeptide that is released in response to perception of stressful stimuli. CRH signaling has been shown to be able to induce increases in amyloid beta (Aβ) peptide levels and tau phosphorylation in mouse models of Aβ pathology. The largest effort towards targeting the CRH signaling pathway has focused on CRH receptor antagonists, Unfortunately, clinical trials implementing these CRH receptor antagonists have been unable to show clinical efficacy. Therefore, while dysregulation of CRH signaling is implicated in a plethora of highly prevalent stress related disorders in addition to AD, receptor- based interventions have not shown to be able to effectively target the pathway in humans. We propose the creation and testing of novel immunotherapeutic approaches to decrease CRH signaling in the brain. Aim 1: Develop anti-CRH immunotherapies and evaluate their ability to engage CRH and block engagement with its high affinity receptor the CRHR1. As our lab has shown that CRH has direct effects on Aβ production12 that are independent of its action on the CRHR1 receptor, we aim to target CRH directly by developing both active vaccines and monoclonal antibodies against CRH. Then evaluate several candidate Anti- CRH monoclonal antibodies and characterize their CRH-neutralizing properties in vitro. We will then take the most promising monoclonal antibodies and convert them to single chain variable fragment (scFv) DNA constructs that we can than transduce in the brains of mice using recombinant Adeno Associated Virus (rAAV). Specific Aim 2: Evaluate ability of immunotherapies to block acute CRH responses in vivo. I will test the ability of the anti-CRH vaccine, monoclonal antibody, and scFv to block acute stress-induced increases in corticosterone in mice following acute or subacute stress. This experiment will test whether these immunotherapies are able to neutralize CRH within the hypophyseal portal system, thereby blocking activation of the Hypothalamic-Pituitary-Axis. This will be followed by testing the ability of our immunotherapies to block acute stress-induced increases in Aβ peptide and tau phosphorylation, evaluating CRH neutralization more broadly throughout the mouse brain. Aim 3: Evaluate the efficacy of active and passive immunotherapeutic approaches in mouse models of Aβ and tau deposition. We intend to test the efficacy of an active vaccine, a monoclonal antibody, and one rAAV scFv construct as therapies in in vivo models relevant to AD. These studies will evaluate the ability of our immunotherapies to block stress-induced exacerbations of Aβ and tau pathologies in CRND8 APP overexpressing and rTg4510 mutant tau overexpressing mouse models.

项目摘要/摘要最近的临床报告表明，慢性心理压力可能会显着 增加患阿尔茨海默病（AD）的风险。压力反应的主要协调者是 促肾上腺皮质激素释放激素（CRH），一种神经肽，在感受到压力时释放。 刺激。CRH信号传导已被证明能够诱导淀粉样β（A β）肽水平的增加， A β病理学小鼠模型中的tau磷酸化。针对CRH信号的最大努力 CRH通路主要集中在CRH受体拮抗剂上，不幸的是，实施这些CRH的临床试验 受体拮抗剂不能显示临床功效。因此，尽管CRH调节异常 除了AD、受体- 基于的干预措施尚未显示出能够有效地针对人类的途径。我们建议 创造和测试新的免疫方法来减少大脑中的CRH信号。 目的1：开发抗CRH免疫疗法并评估其参与CRH和阻断CRH的能力。 与其高亲和力受体CRHR1结合。正如我们的实验室已经表明，CRH有直接影响， A β的产生12与其对CRHR1受体的作用无关，我们的目标是直接靶向CRH， 开发针对CRH的活性疫苗和单克隆抗体。然后评估几个候选反- CRH单克隆抗体，并在体外表征其CRH中和特性。然后我们将采取 最有前途的单克隆抗体，并将其转化为单链可变片段（scFv）DNA构建体 我们可以用重组腺相关病毒（rAAV）在小鼠的大脑中进行复制。 具体目标2：评价免疫疗法在体内阻断急性CRH反应的能力。我将测试 抗CRH疫苗、单克隆抗体和scFv阻断急性应激诱导的CRH增加的能力， 急性或亚急性应激后小鼠的皮质酮。这个实验将测试这些 免疫疗法能够中和垂体门脉系统内的CRH，从而阻断激活 下丘脑-垂体-轴接下来将测试我们的免疫疗法阻断 急性应激诱导的A β肽和tau磷酸化增加，评估CRH中和更多 广泛分布在小鼠大脑中。 目的3：评价主动和被动免疫方法在小鼠模型中的功效， A β和tau沉积。我们打算测试一种活性疫苗、一种单克隆抗体和一种 rAAV scFv构建体作为与AD相关的体内模型中的疗法。这些研究将评估我们 免疫疗法阻断CRND8 APP中应激诱导的A β和tau病理恶化 过表达和rTg4510突变tau过表达小鼠模型。