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.

项目摘要（Kasus-Jacobi项目） 淀粉样蛋白β（Aβ）和晚期糖基化终产物的接收器（RAGE）是核心 阿尔茨海默氏病的发病机理（AD）。没有临床干预措施停止或减慢 疾病可用，但是一些临床试验显示，在认知能力下降方面，结果令人鼓舞 针对Aβ或愤怒时，患有轻度疾病的患者，证明了 利用这些目标进行AD治疗。我们最近发现CAP37，一种阳离子抗菌素 蛋白质在AD，结合和切割Aβ的患者的大脑中受到显着调节，并与 愤怒，这表明CAP37调节AD的发病机理。我们的长期目标是发展安全 以及针对Aβ，愤怒和CAP37的有效治疗方法，用于神经退行性疾病，例如 广告。我们在此应用中的目标是定义CAP37交互的机械和结构方面 愤怒和Aβ。拟议研究的理由是更好地了解CAP37 调节AD发病机理将指导该疾病的新药物的开发。我们提出了两个特定的 目标。我们的第一个目的是定义CAP37-RAGE绑定界面，并确定CAP37如何干扰 该接收器的其他配体的结合。我们针对此目标的工作假设是CAP37结合了愤怒 通过与其他愤怒配体不同的领域。这可能会影响其他配体与愤怒的结合 通过对接收器的变构修改。在此目标中，我们将阐明CAP37和 愤怒。成功完成此目标将使我们到1）提出一个模型，以将CAP37与 相对于Aβ和其他愤怒配体的愤怒，2）确定CAP37与愤怒干扰的结合 其他配体的结合，3）提案一种可能激活cap37的愤怒的机制，4）如果 CAP37激活愤怒，识别具有抑制内源CAP37的治疗潜力的化合物 通过愤怒发出信号。我们的第二个目的是定义CAP37结合的结构决定者和 裂解Aβ并确定CAP37是否会干扰Aβ的聚合，这是最相关的 Aβ的形式。我们将确定CAP37是否结合Aβ单体和/或有毒聚合物，以及是否结合 CAP37防止或逆转Aβ的毒性聚合。我们将定义cap37的机制 最初被预测为非活性，作为Aβ上的丝氨酸蛋白起作用，并确定CAP37是否存在 可以清除聚合的Aβ。实现目标后，我们将知道CAP37的机制 干扰了Aβ-RAGE轴，从而更好地理解CAP37如何影响 AD的进展。这将允许为AD和其他神经退行性的更好的治疗剂开发 涉及Aβ和愤怒的疾病。