Regulation of Virulence Gene Expression in Chlamydia

描述(申请人提供)：衣原体是人类的病原体，可导致不孕不育、失明、肺炎，并与人类的头号死因心脏病密切相关。衣原体是专性细胞内细菌，通过与发病密切相关的两个阶段的发育周期而永久存在。发育周期主要是在转录水平上控制的；然而，我们对衣原体的发育调节机制的理解存在严重的缺陷。我们研究的长期目标是为描述调控衣原体发育和发病机制的关键分子机制做出贡献。我们在这里提出的研究旨在确定衣原体转录因子ChxR的生物学作用和基本调控机制。ChxR是OmpR亚家族反应调节因子中的一个非典型成员。我们的中心假设是，ChxR在调节中晚期基因表达方面具有重要作用，其机制与OmpR/Phob反应调节亚家族相似，但又不同。很大程度上是由于目前衣原体的遗传难治性，ChxR的生物学作用尚不清楚。为了阐明ChxR的生物学作用并确定其调控机制，提出了以下具体目标：1)确定ChxR在体内的直接基因靶点；2)描述ChxR转录激活的机制积分；3)确定ChxR功能所必需的分子内和分子间相互作用。作为这些研究的结果，我们预计将解决该领域的一个基本问题，即衣原体如何调节它们的生长？此外，OmpR反应调节因子，如ChxR，在细菌中广泛存在，在哺乳动物中不存在。因此，它们是开发新抗菌剂的有吸引力的目标。对ChxR用于正常功能的分子机制的表征将使未来能够对干扰ChxR和衣原体感染功能的新分子进行基本设计。 公共卫生相关性：拟议的研究将有助于我们理解如何以及什么控制医学上重要的细菌衣原体的生长和疾病。这项研究的重点是一种调节致病因素的蛋白质。从这项研究中学到的东西将允许未来开发新的抗生素来破坏衣原体致病的能力。

DESCRIPTION (provided by applicant): Chlamydia are human pathogens that cause sterility, blindness, pneumonia and are strongly correlated with the number one cause of death in humans, heart disease. Chlamydia are obligate intracellular bacteria and are perpetuated through a defining biphasic developmental cycle that is intimately linked with pathogenesis. The developmental cycle is governed predominately at the transcriptional level; however, there is a critical deficiency in our understanding of developmental regulatory mechanisms in Chlamydia. The long-term goal in our research is to contribute to a delineation of the key molecular mechanisms that function to regulate chlamydial development and pathogenesis. The research we propose here is designed to define the biological role and essential regulatory mechanisms for the chlamydial transcription factor termed ChxR. ChxR is an atypical member of the OmpR subfamily of response regulators. Our central hypothesis is that ChxR has an important role in regulating middle and late stage gene expression and incorporates a mechanisms similar to, but distinct from, the subfamily of OmpR/PhoB response regulators. Largely due to the current genetic intractability of Chlamydia, the biological role of ChxR is not known. To elucidate the biological role and determine regulatory mechanism of ChxR the following specific aims are proposed: 1) define the direct gene targets of ChxR in vivo, 2) delineate the mechanism integral for chxR transcriptional activation, and 3) determine the intra- and inter- molecular interactions integral to ChxR function. As a result of these studies, we expect to address a fundamental question in the field, 'how do Chlamydia regulate their growth?' Furthermore, OmpR response regulators, like ChxR, are widespread in bacteria and absent in mammals. As such, they are attractive targets for the development of new antimicrobials. Characterization of the molecular mechanisms employed by ChxR for proper function will allow in the future for rationale design of novel molecules that interrupt the function of ChxR and Chlamydia infections. PUBLIC HEALTH RELEVANCE: Proposed studies will facilitate our understanding of how and what controls the growth of and disease by the medically important bacteria, Chlamydia. The focus of this research is a protein that regulates factors that cause disease. What will be learned from this study will allow for future development of new antibiotics to disrupt the ability of Chlamydia to cause disease.