Aberrant immunological phenotypes/functions in the progression of early-onset AgP

描述（由申请人提供）：激活的先天免疫和炎症介导许多疾病的发病机制。关于先天免疫对这些疾病的贡献的新观点可以导致重要的新治疗考虑和治疗目标。我们的研究计划的总体目标是确定免疫机制，异常或其他，这可能是负责一般炎症性疾病的恶化。在这里，我们建议使用一个模型的侵袭性牙周病（AgP），其中异常炎症过程是显而易见的。侵袭性牙周炎是一种罕见、严重且进展迅速的牙周炎，通常遵循简单的家庭传播模式，全球平均患病率约为2% 3 -5。由于侵袭性牙周病的患病率很低，关于这种疾病机制的数据非常缺乏，结果主要基于临床医生的临床经验，而不是对照研究。有趣的是，我们在塔拉哈西一个服务不足的地区确定了一组47名非洲裔美国儿童，他们都在莱昂县的一个卫生部门，被诊断患有中度至重度局部AgP。该应用的一个重要优势是队列在种族、年龄和疾病模式方面的相似性，以及疾病的罕见性和相关和不相关健康对照的可用性。我们推测，这一队列窝藏细菌病原体的免疫反应，导致牙周破坏的严重性和时间增加的异常调节。在这里，我们建议调查细胞/趋化因子的表达，直接和间接地有助于组织破坏和牙周疾病的进展的调节机制。“高反应”表型是指先天免疫系统的炎症反应增加，因此，本提案的一个目的是确定免疫反应中的这种潜在缺陷是否存在于塔拉哈西队列中，以及这种特征是否可以在对牙周病原体的反应中引起。微小RNA（miRNA）调节促炎细胞因子mRNA，并且在LPS刺激后上调。这是合理的，miRNA调节细胞因子的基因表达在牙周疾病中响应于口腔病原体的LPS刺激。因此，该提议的另一个目的是确定miRNA的异常表达是否导致细胞/趋化因子表达的失调，从而导致更侵袭性的疾病进展。重要的是，这些数据将使我们能够为免疫调节领域做出巨大贡献，并将在这个不断发展的领域产生多个研究项目。 公共卫生相关性：免疫系统负责保护我们免受多种类型的伤害，但过度活跃的免疫系统在许多疾病过程中起着重要作用。因此，这是本提案的目标，我们的研究计划，以调查在侵略性牙周病模型中的免疫反应的调节，其中过度活跃的免疫过程是明显的，并在疾病进展中发挥重要作用。在此破译的调节机制将被转化为其他疾病过程，其中包括过度活跃的免疫反应。

DESCRIPTION (provided by applicant): Activated innate immunity and inflammation mediate the pathogenesis of many diseases. New perspectives on the contribution of innate immunity to these diseases, can lead to important new therapeutic considerations and goals for treatment. The overall goal of our research plan is to define immunological mechanisms, aberrant or otherwise, which could be responsible for exacerbation of inflammatory diseases in general. Here we propose to use a model of aggressive periodontal disease (AgP) in which aberrant inflammatory processes are evident. Aggressive periodontitis is a rare, severe and rapidly progressing form of periodontitis usually following a simple pattern of familial transmission with a mean prevalence in the world around 2%3-5. Because the prevalence of aggressive periodontal disease is so low, data about mechanisms of this disease is very scarce and results are based mostly on clinical experience of individual clinicians rather than controlled studies. Interestingly, we have identified a cohort of 47 African-American children in an underserved region of Tallahassee, all within one single health department in Leon County, diagnosed with moderate to severe localized AgP. An important strength of this application is the similarity of the cohort in terms of race, age and pattern of disease coupled with the rarity of the disease and availability of related and unrelated healthy controls. We hypothesize that this cohort harbors aberrant regulation of immunological responses to bacterial pathogens which leads to increased severity and timing of periodontal destruction. Here we propose to investigate regulatory mechanisms of cyto/chemokine expression which directly and indirectly contribute to tissue destruction and periodontal disease progression. The `hyper-responsive' phenotype refers to an increased inflammatory response by the innate immune system, therefore, one objective of this proposal seeks to determine if this underlying defect in the immune response is present in the Tallahassee cohort and if this trait can be elicited in response to periodontal pathogens. Micro RNA (miRNA) regulate pro-inflammatory cytokine mRNA and are up regulated upon LPS stimulation. It is plausible that miRNA regulate cytokine gene expression during periodontal disease in response to LPS stimulation by oral pathogens. Therefore, an additional objective of this proposal is to determine if aberrant expression of miRNA result in dysregulation of cyto/chemokine expression resulting in more aggressive disease progression. Importantly, these data will allow us to contribute greatly to the field of immune regulation, and will spawn multiple research projects in this ever evolving field. PUBLIC HEALTH RELEVANCE: The immune system is responsible for defending us from multiple types of insult, yet an over-active immune system plays a large role in many disease processes. Therefore, it is the goal of this proposal and our research plan to investigate regulation of the immune response in a model of aggressive periodontal disease in which over-active immune processes are evident and play a significant role in disease progression. Regulation mechanisms deciphered here will be translated to other disease processes which incorporate over-active immune responses.