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

基本信息

批准号：
9469597
负责人：
Hunter Futch
金额：
$ 3.57万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/9469597
关键词：
Active Immunotherapy Acute Adrenal Cortex Hormones Adrenal Glands Affect Affinity Alzheimer&apos s Disease Alzheimer&apos 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 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 Research Infrastructure Risk Role Signal Pathway Signal Transduction 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 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

项目摘要

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)，一种因感受到压力而释放的神经肽 CRH 信号传导已被证明能够诱导淀粉样β (Aβ) 肽水平的增加和 Aβ 病理学小鼠模型中的 tau 磷酸化是针对 CRH 信号传导的最大努力。途径主要集中在 CRH 受体拮抗剂上，不幸的是，实施这些 CRH 的临床试验因此，CRH 受体拮抗剂尚未显示出临床疗效。除了 AD 之外，信号传导还与许多高度流行的应激相关疾病有关。基于的干预措施尚未证明能够有效地针对人类的途径。创建和测试减少大脑中 CRH 信号传导的新型免疫治疗方法。目标 1：开发抗 CRH 免疫疗法并评估其参与 CRH 和阻断的能力正如我们的实验室所表明的，CRH 与其高亲和力受体 CRHR1 的结合具有直接影响。 Aβ 的产生12 独立于其对 CRHR1 受体的作用，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，然后评估几种候选抗体。 CRH 单克隆抗体并在体外表征其 CRH 中和特性。最有前途的单克隆抗体并将其转化为单链可变片段 (scFv) DNA 构建体我们可以使用重组腺相关病毒（rAAV）在小鼠大脑中进行转导。具体目标 2：评估免疫疗法阻断体内急性 CRH 反应的能力。抗 CRH 疫苗、单克隆抗体和 scFv 阻断急性应激诱导的能力该实验将测试小鼠在急性或亚急性应激后是否会使用皮质酮。免疫疗法能够中和垂体门静脉系统内的 CRH，从而阻止激活随后将测试我们的免疫疗法的阻断能力。急性应激诱导的 Aβ 肽和 tau 磷酸化增加，更多地评估 CRH 中和作用广泛分布于小鼠大脑。目标 3：评估主动和被动免疫治疗方法在小鼠模型中的疗效我们打算测试一种活性疫苗、一种单克隆抗体和一种抗体的功效。 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的能力。免疫疗法可阻止 CRND8 APP 中应激诱导的 Aβ 和 tau 病理恶化过表达和 rTg4510 突变 tau 过表达小鼠模型。