Natural Product Protease Inhibitors: Therapeutics for Virulence of Oral Pathogens

描述（由申请人提供）：与龈缘和龈下沟相关的口腔感染导致宿主炎症反应。牙龈炎主要是对牙菌斑中的细菌的反应。这种“疾病”在人口中几乎影响到每一个人，在他们一生中的某个时候。牙周炎是一种多因素疾病，包括硬组织和软组织，微生物定植（有/无侵入），炎症反应和适应性免疫反应。牙周炎炎症和组织破坏是由龈下细菌生态的变化引起的，这些变化会引发有害的宿主反应，目前的证据表明，一系列破坏性宿主介质的产生和/或释放发生了改变，从而导致组织破坏。然而，最近的研究已经支持某些假定的口腔病原体产生一系列生理基因产物（例如蛋白酶），其具有接合和刺激各种宿主细胞受体的能力，导致与组织破坏有关的生物分子（例如IL-1 β、TNF 1）的合成显著增强。因此，虽然对抗牙龈炎的策略主要设计为通过机械和/或非特异性抗微生物疗法来管理，以降低菌斑中细菌挑战的总体程度;但靶向牙周炎需要相对于生物膜的微生物组成的独特特征以及可能对这些病原体独特的潜在关键宿主细胞信号传导机制的额外考虑。这项STTR提案的重点是确定天然植物基制剂的策略，这些制剂将抑制来自重要口腔病原体牙龈卟啉单胞菌、T。denticola和T.艾西娅这些蛋白酶已被证明与疾病部位、体外生长和存活、炎症介质的产生和体内毒力有关。因此，干扰这些关键分子的活性应该提供一种创新的新策略，以生物学方式干扰这些口腔病原体引起的感染和疾病过程。牙龈炎和牙周炎影响与人类已知的任何疾病一样大的全球人口比例。因此，鉴定和开发针对慢性感染和炎症方面的更有效的治疗方案将为这些个体提供显著的益处。具体目的是记录选择的天然产物对这些细菌的生长，宿主细胞触发和毒力能力的影响。 公共卫生相关性：该STTR提案旨在评估天然产品通过开发牙龈炎症和组织破坏的治疗方法来改善口腔健康的能力。具体目标是分离和分析具有抗蛋白酶特性的天然产物，以治疗口腔感染/疾病。

DESCRIPTION (provided by applicant): Oral infections associated with the gingival margin and subgingival sulcus lead to host inflammatory responses. Gingivitis is primarily a response to the bacteria in plaque. This "disease" affects nearly everyone in the population, at some time during their life. Periodontitis is a multifactorial disease that encompasses the hard and soft tissue, microbial colonization (with/without invasion), inflammatory responses, and adaptive immune responses. Periodontal inflammation and tissue destruction result from variations in the subgingival bacterial ecology that trigger deleterious host responses, with current evidence suggesting altered production and/or release of an array of destructive host mediators that lead to tissue destruction. However, recent studies have supported that certain putative oral pathogens produce a array of physiologic gene products (e.g. proteases) that have the capacity to engage and stimulate various host cell receptors resulting in a substantially enhanced synthesis of biomolecules that have been implicated in tissue destruction (e.g. IL-1ss, TNF1). Thus, while strategies of combating gingivitis are primarily designed to be managed by mechanical and/or nonspecific antimicrobial therapies to decrease the overall magnitude of bacterial challenge in the plaque; targeting periodontitis requires additional considerations relative to unique features of the microbial composition of the biofilms, and potentially critical host cell signaling mechanisms that may be unique to these pathogens. This STTR proposal is focusing on a strategy to identify natural plant-based agents that will inhibit proteases from significant oral pathogens, P. gingivalis, T. denticola, and T. forsythia. These proteases have been shown to relate to disease sites, in vitro growth and survival, production of inflammatory mediators, and in vivo virulence. Thus, interfering with the activity of these crucial molecules should provide an innovative new strategy to biologically interfere with infection and disease processes provoked by these oral pathogens. Gingivitis and periodontitis affect as large a proportion of the global population as any disease(s) known to mankind. Thus, identifying and developing more effective therapeutic regimens targeting aspects of the chronic infection and inflammation would provide a significant benefit to these individuals. Specific Aims are to document the effect of select natural products on the growth, host cell triggering, and virulence capacity of these bacteria. PUBLIC HEALTH RELEVANCE: This STTR proposal aims to evaluate natural products for their ability to improve oral health by developing therapeutic treatments for gingival inflammation and tissue distruction. Specific Aims are to isolate and analyze natural products with anti-proteases properties to treat oral infections/diseases.