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Effect of APP copy number variants in Alzheimer's disease and and Down Syndrome on Reelin expression and function

阿尔茨海默病和唐氏综合症中 APP 拷贝数变异对 Reelin 表达和功能的影响

基本信息

批准号：
10760161
负责人：
Laurent Calvier
金额：
$ 26万
依托单位：
REELIN THERAPEUTICS, INC.
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：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760161
关键词：
Adhesions Affinity Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Precursor Amyotrophic Lateral Sclerosis Antibodies Apolipoproteins Astrocytes Binding Biological Blood Vessels Brain Cell Adhesion Molecules Cell physiology Cells Chromosome 21 Chronic Copy Number Polymorphism DAB2 gene Data Degenerative Disorder Dementia Disease Disease Progression Down Syndrome E-Selectin Early Onset Alzheimer Disease Effectiveness Endothelial Cells Etiology Extracellular Matrix Proteins Extravasation Foundations Future Grant Histologic Human Immune Immunologic Receptors Individual Infiltration Inflammation Inflammatory Intercellular adhesion molecule 1 Intervention Invaded Lead Leukocyte Adhesion Molecules Leukocytes Mediating Methods Microglia Modeling Monoclonal Antibodies Mus Neurodegenerative Disorders Neurons Parkinson Disease Pathology Pathway interactions Patients Plasma Plasma Proteins Preclinical Testing Process Proteins Risk Factors Role Senile Plaques Site Source System Testing Therapeutic Tissues Trisomy Vascular Cell Adhesion Molecule-1 Vascular Endothelium apolipoprotein E receptor 2 cell type human model inflammatory milieu mouse model neuroinflammation new therapeutic target novel overexpression preclinical development prevent receptor recruit response therapeutic development

项目摘要

Abstract Chronic inflammatory pathology represents a major source of damage to the brain observed in Down’s syndrome (DS). Although the precise etiology of these diseases is often unknown, excessive leukocyte extravasation is a substantial contributor to the tissue damage/inflammation and our recent data show a prominent role of the plasma protein, Reelin in this process. Furthermore, we have now shown that it is possible, using anti-Reelin monoclonal antibodies, to deplete the plasma of Reelin, which results in a significant reduction of a wide range of vascular adhesion molecule expression. Thus, in contrast to the current methods of depleting individual adhesion molecules or immune receptors, our anti-Reelin approach systematically downregulates all major inflammation-driven adhesion proteins on the vascular endothelium. The purpose of this proposal is to demonstrate the role of Reelin in DS by 1) validating the therapeutic potential of mitigating chronic inflammatory milieu with an anti-Reelin antibody in an DS mouse model and 2) identifying high affinity Reelin antibodies for future therapeutic development.

摘要慢性炎症病理是脑损伤的主要来源，观察到唐氏综合征(DS)。尽管这些疾病的确切病因通常是未知的，过度的白细胞外渗是组织损伤/炎症的重要因素我们最近的数据显示，血浆蛋白Reelin在这一过程中发挥了突出的作用。此外，我们现在已经证明，使用抗Reelin单抗，有可能耗尽血浆中的Reelin，从而显著减少广泛的血管黏附分子的表达。因此，与目前耗尽个体的方法相比，黏附分子或免疫受体，我们的抗Reelin方法是系统的下调血管内皮细胞上所有主要的炎症驱动的黏附蛋白。本提案的目的是通过1)验证Reelin在DS中的作用抗Reelin抗体对慢性炎症环境的治疗作用 DS小鼠模型和2)鉴定用于未来治疗的高亲和力Reelin抗体发展。