Anti-medin immunotherapy for vascular aging and related dementias

针对血管老化和相关痴呆的抗 Medin 免疫疗法

基本信息

批准号：
10724869
负责人：
Raymond Quezon Migrino
金额：
$ 38.01万
依托单位：
ARIZONA VETERANS RESEARCH AND EDUCATION FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724869
关键词：
Acceleration Affinity Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amino Acids Amyloidosis Antigens Aortic Aneurysm Attenuated Autoimmunity Biochemistry Blood Vessels Brain Pathology C-terminal C57BL/6 Mouse Cerebrovascular Disorders Clinical Data Data Dementia Development Disease Dose EGF gene Endothelial Cells Endothelium Epidemiology Epitopes Functional disorder Gene Proteins Goals Human Immunization Immunology Immunotherapy Impaired cognition Impairment In Vitro Inbred BALB C Mice Inflammatory Keyhole Limpet Hemocyanin Knock-out L Forms Late Onset Alzheimer Disease Length Monoclonal Antibodies Mus Pathology Peptides Proteins Regimen Research Risk Factors Stress Tertiary Protein Structure Testing Toxic effect Vaccination Vaccine Design Vaccines Vascular Dementia Vascular Diseases aged amyloid formation antibody immunotherapy cerebrovascular cerebrovascular biology cognitive function cytotoxicity design effective therapy efficacy evaluation efficacy testing endothelial dysfunction feasibility testing immunogenicity in vivo in vivo evaluation innovation medin member milk fat globule mouse model multidisciplinary neuroinflammation neuropathology neurovascular novel novel therapeutic intervention pilot test polyclonal antibody pre-clinical preservation prevent response senescence sialogangliosides vaccine development vascular inflammation

Acceleration Affinity Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amino Acids Amyloidosis Antigens Aortic Aneurysm Attenuated Autoimmunity Biochemistry Blood Vessels Brain Pathology C-terminal C57BL/6 Mouse Cerebrovascular Disorders Clinical Data Data Dementia Development Disease Dose EGF gene Endothelial Cells Endothelium Epidemiology Epitopes Functional disorder Gene Proteins Goals Human Immunization Immunology Immunotherapy Impaired cognition Impairment In Vitro Inbred BALB C Mice Inflammatory Keyhole Limpet Hemocyanin Knock-out L Forms Late Onset Alzheimer Disease Length Monoclonal Antibodies Mus Pathology Peptides Proteins Regimen Research Risk Factors Stress Tertiary Protein Structure Testing Toxic effect Vaccination Vaccine Design Vaccines Vascular Dementia Vascular Diseases aged amyloid formation antibody immunotherapy cerebrovascular cerebrovascular biology cognitive function cytotoxicity design effective therapy efficacy evaluation efficacy testing endothelial dysfunction feasibility testing immunogenicity in vivo in vivo evaluation innovation medin member milk fat globule mouse model multidisciplinary neuroinflammation neuropathology neurovascular novel novel therapeutic intervention pilot test polyclonal antibody pre-clinical preservation prevent response senescence sialogangliosides vaccine development vascular inflammation

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项目摘要

ABSTRACT Age is the most important risk factor for cardio-cerebrovascular diseases (CVD) and dementia disorders. Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia disorders, including Alzheimer's disease (AD) and AD-related dementias (ADRD) such as vascular dementia (VaD). Indeed, unbiased data-driven analyses showed that vascular dysfunction is the earliest and strongest brain pathology associated with late onset AD. There is growing evidence that medin, a 50-amino acid peptide that forms one of the most common yet least studied human amyloidoses, is an important driver of vascular aging pathologies. We and others showed that vascular medin burden was associated with VaD, AD and aortic aneurysms. Medin, a cleavage product of milk fat globule-EGF factor 8 protein (MFGE8), accumulates in vessels with aging, causes endothelial dysfunction through oxidative and nitrative stress and induces endothelial pro- inflammatory activation that could initiate neuroinflammation. Knockout of MFGE8 domain containing medin prevented cerebrovascular medin amyloid formation and restored cerebrovascular function. We designed and produced an immunogen modified from the aggregation-prone C terminus of medin to be used as anti-medin vaccine and 3 monoclonal antibodies (mAbs) that have high medin affinity. Our overall goal is to evaluate anti- medin immunotherapy using medin vaccination (Aim 1) and anti-medin mAbs (Aim 2) to attenuate or prevent medin-induced vascular dysfunction and neurovascular pathology in aging C57BL/6 mice and in senescence accelerated mouse-prone 8 (SAMP8) mice. Aim 1 is to develop and test the benefit of anti-medin vaccination in preventing cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. We will first determine an optimal vaccination regimen and then test the efficacy of that regimen. Aim 2 is to develop and pilot test anti-medin mAb immunotherapy to attenuate medin-induced cerebrovascular and cognitive dysfunction and neurovascular pathology in C57BL/6 aged and SAMP8 mice. First, we will determine which mAb (19H1, 6F2 and 13B7) will have the best effect in reversing medin-induced endothelial cytotoxicity. Next, we will do pilot feasibility in vivo testing of the ideal dosing of anti-medin mAbs to reduce cerebrovascular medin and preserve cerebrovascular and cognitive function. The proposal is innovative and paradigm-changing in potentially establishing medin as a new target for vascular disease and dementia, and anti-medin immunotherapy as a potential new treatment approach for vascular aging and resulting pathologies.

抽象的年龄是心脏脑血管疾病（CVD）和痴呆症疾病的最重要危险因素。流行病学，临床前和临床数据表明，血管疾病与痴呆症密切相关疾病，包括阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRD），例如血管性痴呆（vad）。确实，无偏的数据驱动分析表明，血管功能障碍是最早，最强的脑病理学与晚期AD相关。越来越多的证据表明Medin是50个氨基酸肽这构成了最常见研究的人类淀粉样蛋白是血管的重要驱动力之一衰老的病理。我们和其他人表明，血管Medin负担与VAD，AD和主动脉有关动脉瘤。 Medin是牛奶脂肪球-EGF因子8蛋白（MFGE8）的裂解产物，它积聚在血管中随着衰老，通过氧化和硝化应激引起内皮功能障碍，并诱导内皮促疾病炎症激活可能引发神经炎症。 MFGE8域的敲除含有Medin的域防止脑血管降解淀粉样蛋白形成并恢复脑血管功能。我们设计了产生了一种从易于聚集的Medin的C末端修饰的免疫原，以用作抗媒体具有高MEDIN亲和力的疫苗和3种单克隆抗体（mAb）。我们的总体目标是评估反 - 使用MEDIN疫苗接种（AIM 1）和抗媒体MAB（AIM 2）的Medin免疫疗法以减弱或预防衰老C57BL/6小鼠的Medin诱导的血管功能障碍和神经血管病理学加速的小鼠易发8（SAMP8）小鼠。目的1是开发和测试抗中毒疫苗接种的好处防止脑血管和认知功能障碍以及C57BL/6年龄的神经血管病理 SAMP8小鼠。我们将首先确定最佳疫苗接种方案，然后测试该方案的功效。 AIM 2是开发和进行试验测试抗中毒MAB免疫疗法，以减轻Medin诱导的脑血管 C57BL/6年龄和SAMP8小鼠的认知功能障碍和神经血管病理学。首先，我们会的确定哪个mAB（19H1、6F2和13B7）将在逆转Medin诱导的内皮方面具有最佳效果细胞毒性。下一脑血管Medin并保留脑血管和认知功能。该提案是创新的，在可能建立Medin作为血管疾病和痴呆症的新目标和范式方面改变范式抗中毒免疫疗法是一种潜在的血管衰老和导致病理学的新方法。