ELUCIDATING & DISRUPTING PLASMODIUM ERYTHROCYTE-BINDING LIKE LIGAND INTERACTIONS

描述（由申请人提供）：在理解疟原虫入侵红细胞所需的相互作用方面存在根本性的差距。我们的长期目标是确定受体-配体在红细胞侵袭过程中的相互作用是如何在分子水平上介导的，以及它们如何被用于预防、治疗和诊断目的。本应用的目的是了解红细胞结合样（EBL）家族受体识别的分子基础，并建立针对该家族的中和性单克隆抗体的抑制模式。该应用程序的中心假设是EBL家族成员的结合域（DBL结构域）具有二聚化的保守折叠，创建用于识别各种受体的受体结合口袋和通道，并且抑制性抗体通过阻止它们的形成或它们的可及性来靶向结合口袋和通道。拟议研究的基本原理是，一旦确定了EBL家族成员的功能区域，这些区域就可以用于疫苗设计、新的基于蛋白质的治疗和/或诊断。因此，拟议的研究与NIH开发可能减轻人类疾病负担的基础知识的使命有关。此外，本研究将促进我们对受体-配体相互作用、配体-抗体相互作用和微生物发病机制的理解。在强有力的初步数据支持下，这一假设将通过追求两个具体目标来验证：1)确定EBL家族成员的受体结合袋；2)确定中和抗体如何结合DBL结构域并抑制入侵。在第一个目标下，结构、体外和体内研究将用于全面确定EBL家族介导的相互作用的分子细节。在第二个目标下，结构和相互作用作图研究将揭示由中和抗体靶向的EBL家族表位，以确定具有最大中和潜力的表位。这项拟议的研究意义重大，因为它有望推进和扩大我们对受体-配体和配体-抗体相互作用的理解，并为开发疟疾诊断、预防和治疗干预措施提供所需的知识。公共卫生相关性：拟议的研究解决了疟疾宿主-病原体相互作用的一个重要且未被充分研究的领域，该领域适用于预防疟原虫寄生虫的红细胞入侵。这项拟议的研究与公共卫生有关，因为红细胞入侵是疟疾疾病发展的关键步骤。因此，这些发现有望适用于人类健康，因为它们可以用于疟疾的新治疗和诊断。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding of interactions required for erythrocyte invasion by Plasmodium parasites. Our long-term goal is to determine how receptor-ligand interactions during erythrocyte invasion are mediated at the molecular level and how they can be exploited for preventative, therapeutic and diagnostic purposes. The objectives of this application are to understand the molecular basis of receptor recognition by the Erythrocyte-binding like (EBL) family and to establish the mode of inhibition of neutralizing monoclonal antibodies that target this family. The central hypothesis of the application is that the binding domains (DBL domains) of EBL family members possess a conserved fold that dimerizes, creating receptor-binding pockets and channels that are used to recognize a variety of receptors, and that inhibitory antibodies target binding pockets and channels either by preventing their formation or their accessibility. The rationale for the proposed research is that once the functional regions of the EBL family members have been determined these can be exploited for vaccine design, novel protein-based therapeutics and/or diagnostics. Thus, the proposed research is relevant to that part of the NIH's mission of developing fundamental knowledge that may reduce the burden of human disease. In addition, the proposed research will advance our understanding of receptor-ligand interactions, ligand-antibody interactions and microbial pathogenesis. Supported by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the receptor binding pockets of the EBL family members; and 2) Determine how neutralizing antibodies bind to DBL domains and inhibit invasion. Under the first aim, structural, in vitro and in vivo studies will be used to comprehensively determine the molecular details of interactions mediated by the EBL family. Under the second aim, structural and interaction mapping studies will reveal epitopes of the EBL family targeted by neutralizing antibodies towards identifying epitopes that have the greatest neutralizing potential. The proposed research is significant because it is expected to advance and expand our understanding of receptor-ligand and ligand-antibody interactions and to provide the knowledge required to develop diagnostics, preventative and therapeutic interventions for malaria. PUBLIC HEALTH RELEVANCE: The proposed studies address an important and under-investigated area of malaria host-pathogen interactions that has applicability to preventing red blood cell invasion by Plasmodium parasites. The proposed research has relevance to public health, because red blood cell invasion is a critical step in the progression of the disease, Malaria. Thus, the findings are expected to be applicable to the health of human beings as they could be exploited for novel treatments and diagnostics for Malaria.