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.

项目概要（Kasus-Jacobi项目） 淀粉样蛋白β（Aβ）和晚期糖基化终末产物受体（AGEs）是糖基化过程的核心。 阿尔茨海默病（AD）的发病机制。没有临床干预来阻止或减缓 疾病是可用的，但一些临床试验显示，令人鼓舞的结果方面的认知下降， 当靶向Aβ或A β时，患有轻度疾病的患者， 利用这些靶点进行AD治疗。我们最近发现，阳离子抗菌剂CAP 37 蛋白质，在AD患者的大脑中显著上调，结合和切割Aβ，并与 这表明CAP 37调节AD的发病机制。我们的长期目标是发展安全的 以及针对神经退行性疾病的Aβ、CAP 37和CAP 37的有效治疗方法， AD.我们的目的是在这个应用程序中，以确定的机制和结构方面的CAP 37的相互作用 和Aβ。拟议研究的基本原理是，更好地了解CAP 37 调节AD发病机制将指导该病新药的开发。我们提出两个具体的 目标。我们的第一个目标是定义CAP 37-β-内酰胺酶结合界面，并确定CAP 37如何干扰β-内酰胺酶。 该受体的其他配体的结合。我们对此的工作假设是，CAP 37结合了 通过与其他配体不同的结构域。这可能会影响其他配体与E2的结合 通过受体的变构修饰。在这个目标中，我们将阐明由CAP 37形成的复合物， - 是的这一目标的成功完成将使我们能够：1）提出一种结合CAP 37的模型， 2）确定CAP 37与Aβ和其他β-内酰胺酶配体的结合如何干扰Aβ和其他β-内酰胺酶配体， 其他配体的结合，3）提出了CAP 37可能激活BMPs的机制，和4）如果 CAP 37激活RAGE，鉴定具有抑制内源性CAP 37治疗潜力的化合物 通过网络发送信号。我们的第二个目标是确定CAP 37结合的结构决定因素， Aβ的切割并确定CAP 37是否干扰Aβ的聚合，这是最相关的 AD中的Aβ。我们将确定CAP 37是否结合Aβ单体和/或毒性聚合物， CAP 37可阻止或逆转Aβ的毒性聚合。我们将定义CAP 37的机制， 最初预测为无酶活性，作为Aβ上的丝氨酸蛋白酶起作用，并确定CAP 37是否 可以切割聚合的Aβ。当我们的目标实现时，我们将知道CAP 37的机制。 干扰Aβ-淀粉样蛋白轴，从而更好地了解CAP 37如何影响Aβ-淀粉样蛋白轴。 AD的进展。这将使开发更好的治疗AD和其他神经退行性疾病的药物成为可能。 涉及Aβ和A β的疾病。