Structural Approach to Define New Functional Activities of Neutrophil Protein CAP37 in Neurodegenerative Diseases(Kasus-Jacobi)

定义中性粒细胞蛋白 CAP37 在神经退行性疾病中新功能活性的结构方法（Kasus-Jacobi）

• 批准号: 9360241
• 负责人: Anne Kasus-Jacobi
• 金额: $ 20.66万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9360241
• 关键词: Affect; Age related macular degeneration; Alzheimer' s Disease; Amyloid beta-Protein; Binding; Brain; Cations; Centers of Research Excellence; Cleaved cell; Clinical; Clinical Trials; Complex; Complications of Diabetes Mellitus; Dementia; Development; Diabetic Retinopathy; Disease; Disease Progression; Goals; Impaired cognition; Inflammatory; Intervention; Ligands; Malignant neoplasm of pancreas; Mediator of activation protein; Modeling; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Oklahoma; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Polymers; Proteins; Receptor Activation; Research; Role; Serine Protease; Signal Transduction; Testing; Therapeutic; Treatment Efficacy; United States; abeta accumulation; antimicrobial; base; cationic antimicrobial protein CAP 37; cytotoxicity; malignant breast neoplasm; monomer; neutrophil; novel therapeutics; physical state; polymerization; prevent; receptor; receptor binding; receptor for advanced glycation endproducts; structural biology; success

Project Summary (Kasus-Jacobi Project) Amyloid beta (Aβ) and the receptor for advanced glycation end-products (RAGE) are central to the pathogenesis of Alzheimer's disease (AD). No clinical intervention to stop or slow the progression of the disease is available, but a few clinical trials revealed encouraging results in terms of cognitive decline for patients with a mild form of the disease when Aβ or RAGE were targeted, demonstrating the validity of exploiting these targets for AD treatment. We have recently discovered that CAP37, a cationic antimicrobial protein, is significantly up regulated in the brains of patients with AD, binds and cleaves Aβ, and interacts with RAGE, which suggests that CAP37 modulates the pathogenesis of AD. Our long-term goal is to develop safe and effective therapeutic approaches targeting Aβ, RAGE and CAP37 for neurodegenerative diseases such as AD. Our objective in this application is to define the mechanistic and structural aspects of CAP37's interactions with RAGE and Aβ. The rationale for the proposed research is that a better understanding of how CAP37 regulates AD pathogenesis will guide the development of new drugs for the disease. We propose two specific aims. Our first aim is to define the CAP37-RAGE binding interface and determine how CAP37 interferes with the binding of other ligands of this receptor. Our working hypothesis for this aim is that CAP37 binds RAGE through a different domain than the other RAGE ligands. This may affect the binding of other ligands to RAGE through allosteric modification of the receptor. In this aim, we will elucidate the complex formed by CAP37 and RAGE. Successful completion of this aim will allow us to 1) propose a model for the binding of CAP37 to RAGE relative to Aβ and other RAGE ligands, 2) determine how the binding of CAP37 to RAGE interferes with the binding of other ligands, 3) propose a mechanism for a possible activation of RAGE by CAP37, and 4) if CAP37 activates RAGE, identify compounds with therapeutic potential for inhibition of endogenous CAP37 signaling through RAGE. Our second aim is to define the structural determinants of CAP37's binding and cleavage of Aβ and determine if CAP37 interferes with the polymerization of Aβ, which is the most relevant form of Aβ in AD. We will determine if CAP37 binds Aβ monomers and/or toxic polymers, and if the binding of CAP37 prevents or reverses the toxic polymerization of Aβ. We will define the mechanism by which CAP37, originally predicted to be enzymatically inactive, operates as a serine protease on Aβ, and determine if CAP37 can cleave polymerized Aβ. When our aims are accomplished, we will know the mechanisms by which CAP37 interferes with the Aβ-RAGE axis, leading to a better appreciation of how CAP37 might influence the progression of AD. This will allow the development of better therapeutics for AD and other neurodegenerative diseases involving Aβ and RAGE.

项目概述（Kasus-Jacobi项目）