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：
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
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/9765429
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 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

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氏病（AD）的风险。压力反应的主要协调员是皮质激素释放的马酮（CRH），一种神经肽，响应于压力的感知而释放刺激。 CRH信号传导已被证明能够诱导淀粉样蛋白β（Aβ）胡椒水平的增加，并且 Aβ病理小鼠模型中的tau磷酸化。针对CRH信号的最大努力不幸的是，途径专注于CRH受体拮抗剂，实施这些CRH的临床试验受体拮抗剂无法显示临床效率。因此，CRH的失调除了AD，接收器 - 基于干预措施尚未证明能够有效地针对人类的途径。我们建议新型免疫治疗方法的创建和测试可减少大脑中的CRH信号传导。目标1：开发抗CRH免疫疗法并评估其参与CRH和阻止的能力与其高亲和力接收器互动CRHR1。正如我们的实验室表明CRH对 Aβ产生112独立于其对CRHR1受体的作用，我们的目标是直接靶向CRH 开发了活性疫苗和针对CRH的单克隆抗体。然后评估几个候选人反 - CRH单克隆抗体并在体外表征其CRH中和性特性。然后，我们将接受最有希望的单克隆抗体，并将其转换为单链可变片段（SCFV）DNA构建体我们可以使用重组adeno相关病毒（RAAV）在小鼠的大脑中转导。具体目标2：评估免疫疗法阻止体内急性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增加的能力急性或亚急性应激后小鼠的皮质酮。该实验将测试是否免疫疗法能够中和垂体门户系统中的CRH，从而阻止激活下丘脑 - 垂体轴的。随后将测试我们的免疫疗法阻止的能力急性应激诱导的Aβ肽和tau磷酸化的增加，评估CRH神经模拟更多在整个小鼠大脑中广泛。目标3：评估在小鼠模型中主动和被动免疫治疗方法的效率 Aβ和TAU沉积。我们打算测试活性疫苗的效率，单克隆抗体和一种 RAAV SCFV构造是与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以阻止CRND8 APP中Aβ和TAU病理的应力诱导的加重过表达和RTG4510突变体Tau过表达的小鼠模型。