Antibacterial Peptides and Zinc in Innate Immunity and Mammalian Physiology

描述（由申请人提供） 摘要：哺乳动物先天免疫系统对微生物入侵提供非特异性和立即的反应，构成调节宿主/病原体相互作用并防止疾病发作的原始防御机制。核糖体合成的抗微生物肽是先天免疫应答的普遍存在的组分，保护粘膜表面免受细菌入侵。在释放到细胞外空间后，许多抗微生物肽通过穿透和破坏细菌细胞的外膜来发挥非特异性抗菌作用。我们认为，这些肽存在额外的和未被认识的作用，我们有动机阐明抗菌肽如何有助于宿主生理之前，他们的细胞外释放。基于结构和细胞定位，我们假设选择抗菌肽是调节锌稳态的关键参与者。该提案的中心目标是在分子和生理水平上鉴定和研究基于核糖体肽的抗生素和锌之间的协同作用。我们提出了一个多方面的实验计划，利用无机化学和细胞生物学（i）解决肽，金属离子，其他生物分子和推定的细胞靶点之间的相互作用，以及（ii）破译宿主和微生物病原体的下游生理后果。这一举措是重要的和创新的，因为它提供了一个全新的框架，考虑抗菌肽和金属离子商店，后者是必不可少的，但往往被忽视的免疫反应和抗菌治疗的发展。这些研究将增强我们对金属离子生理学和宿主/病原体相互作用的基本机制的理解，从而影响生物医学，药物化学和公共卫生领域。) 公共卫生相关性：这项研究计划位于化学/生物学/医学界面，解决了人类先天免疫和粘膜防御的基本机制，并寻求建立抗菌肽和锌生物学之间未被认识的联系。拟议的调查结果将提供重要的新见解哺乳动物的免疫反应，宿主/病原体的相互作用，和金属离子的生理。这项基础研究与公共卫生有关;阐明生理学基础的化学和生物学对于提高我们对人类健康和防治疾病的理解至关重要。

DESCRIPTION (Provided by the applicant) Abstract: The mammalian innate immune system provides non-specific and immediate responses to microbial invasion, constituting a primitive defense mechanism that modulates host/pathogen interactions and prevents the onset of disease. Ribosomally-synthesized antimicrobial peptides are ubiquitous components of the innate immune response, protecting mucosal surfaces from bacterial invasion. Following release into the extracellular space, many antimicrobial peptides exert non-specific antibacterial action by penetrating and disrupting the outer membranes of bacterial cells. We believe that additional and unrecognized roles for these peptides exist and we are motivated to elucidate how antimicrobial peptides contribute to host physiology prior to their extracellular release. Based on structures and cellular localizations, we hypothesize that select antimicrobial peptides are key players in regulating zinc homeostasis. A central goal of this proposal is to identify and investigate synergies between ribosomal peptide-based antibiotics and zinc at the molecular and physiological levels. We present a multifaceted experimental program that draws upon inorganic chemistry and cell biology to (i) address interactions between peptides, metal ions, other biomolecules and putative cellular targets, and (ii) decipher the downstream physiological consequences for the host and microbial pathogens. This initiative is significant and innovative because it provides a completely new framework for considering antimicrobial peptides and metal ion stores, that latter of which are essential but oftentimes overlooked in the contexts of the immune response and antibacterial therapeutic development. These studies will enhance our understanding of fundamental mechanisms that underlie metal ion physiology and the host/pathogen interaction and thereby impact the fields of biomedicine, medicinal chemistry, and public health. ) Public Health Relevance: This research initiative lies at the chemistry/biology/medicine interface, addresses fundamental mechanisms of human innate immunity and mucosal defense, and seeks to establish unrecognized connections between antimicrobial peptides and zinc biology. The outcomes of the proposed investigations will afford important new insights into the mammalian immune response, the host/pathogen interaction, and metal ion physiology. This basic research is relevant to public health; elucidating the chemistry and biology that underlies physiology is essential for improving our understanding of human health and combating disease.