ELUCIDATING & DISRUPTING PLASMODIUM ERYTHROCYTE-BINDING LIKE LIGAND INTERACTIONS

描述(由申请人提供)：在了解疟原虫入侵红细胞所需的相互作用方面存在着根本的差距。我们的长期目标是确定在红细胞入侵过程中受体-配体的相互作用是如何在分子水平上调节的，以及如何将其用于预防、治疗和诊断目的。本应用的目的是了解红细胞结合样受体(EBL)家族识别受体的分子基础，并建立针对该家族的中和性单抗的抑制模式。该应用的中心假设是，EBL家族成员的结合结构域(DBL结构域)具有一个保守的折叠，该折叠可二聚化，创建用于识别各种受体的受体结合口袋和通道，而抑制性抗体通过阻止结合口袋和通道的形成或其可及性来靶向结合口袋和通道。这项拟议研究的基本原理是，一旦确定了EBL家族成员的功能区，就可以利用这些功能区进行疫苗设计、新的基于蛋白质的疗法和/或诊断。因此，这项拟议的研究与美国国立卫生研究院开发基础知识以减轻人类疾病负担的使命部分相关。此外，这项研究还将促进我们对受体-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。在强大的初步数据的支持下，这一假说将通过追求两个特定的目标来检验：1)确定EBL家族成员的受体结合口袋；2)确定中和抗体如何与DBL结构域结合并抑制侵袭。在第一个目标下，结构、体外和体内研究将被用来全面确定EBL家族介导的相互作用的分子细节。在第二个目标下，结构和相互作用图谱研究将揭示EBL家族的表位，以中和抗体为靶点，以确定具有最大中和潜力的表位。拟议的研究具有重要意义，因为它有望促进和扩大我们对受体-配体和配体-抗体相互作用的理解，并提供制定疟疾诊断、预防和治疗干预措施所需的知识。公共卫生相关性：拟议的研究涉及疟疾宿主-病原体相互作用的一个重要且研究不足的领域，该领域适用于防止疟原虫入侵红细胞。这项拟议的研究与公共健康相关，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，因为它们可以被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.