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Cytotoxic mechanisms of Aggregatibacter actinomycetemcomitans leukotoxin

放线菌白毒素聚集杆菌的细胞毒机制

基本信息

批准号：
8475589
负责人：
Angela C. Brown
金额：
$ 7.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475589
关键词：
Actinobacillus actinomycetemcomitans Affect Area Bacteria Bacterial Proteins Behavior Binding Biological Cell membrane Cells Cercopithecidae Child Cholesterol Clinical Data Complex Cosmetics Cytosol Defect Deformity Development Devices Disease Disease Progression Drug Delivery Systems Elements Engineering Environment Faculty Family Grant Host Defense Mechanism Human Immune Immune response Infection Infective endocarditis Intervention Lead Leukocytes Lipids Literature Membrane Membrane Microdomains Mentors Pathogenesis Peptides Periodontal Diseases Periodontal Ligament Periodontitis Pharmaceutical Preparations Phase Play Pongidae Positioning Attribute Primates Principal Investigator Process Proteins Research Research Personnel Role Structure Systemic infection Tail Targeted Toxins Techniques Therapeutic Therapeutic Agents Tooth Loss Tooth structure Toxic effect Toxin Training United States Virulence Factors Work Writing alveolar bone base career cellular targeting cytolethal distending toxin cytotoxic cytotoxicity design killings leukotoxin man medically underserved member microbial novel therapeutics pathogen phase change porin prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): Aggregatibacter ctinomycetemcomitans is a Gram-negative pathogen that is the etiologic agent of localized aggressive periodontitis (LAP) and other systemic infections, including infective endocarditis. LAP, which affects medically-underserved children in both the United States and throughout the world, is characterized by a breakdown of the periodontal ligament and alveolar bone structure that holds the teeth in place. Without intervention, loss of teeth occurs, causing both a cosmetic deformity and a functional defect. The manner in which A. actinomycetemcomitans causes LAP is not known; however, it is known that it produces several putative virulence factors, including a leukotoxin (LtxA), a member of the repeats-in-toxin (RTX) family. Based on experimental and clinical data, LtxA is believed to be a primary virulence factor for the bacterium. Thus, preventing or interfering with LtxA activity may be one option for treatment of disease. The toxin kills human and primate white blood cells and likely plays a role in A. actinomycetemcomitans evasion of the immune response during infection. It has been demonstrated that in its initial response with the host cell membrane, LtxA does not form a pore, but rather destabilizes the membrane. Additionally, LtxA is internalized within the cell, where it binds to the intracellular region of its receptor. In the mentored phase of this study, we will investigate the mechanisms of these two findings. In our first aim, we will identify the structural domains of LtxA that are responsible for membrane destabilization. The second aim will allow us to define the mechanism of internalization and determine the structural domains of LtxA that are responsible for internalization. In the independent phase of the study, these mechanisms and structural domains will be exploited in the design of therapeutic devices. In the third aim, a device to block LtxA activity by interfering with the cellular targets of the toxin will be developed. In the fourth aim, the internalization mechanism of LtxA will be utilized in the design of a drug-delivery device to carry a drug directly to the cytosol of a cell. The research will answer vital questions about the mechanisms by which LtxA kills host cells. In addition, the work will lead to the development of therapeutic agents, on with specific activity against LtxA and RTX toxicity and another with more general applications. During this work, the principal investigator will be trained in the necessary biological techniques during the mentored phase of the research that will be vital to her planned career as an independent investigator in microbial pathogenesis. Other elements of the proposed training plan, such as coursework, grant-writing, and a mentored faculty position search, will allow the principal investigator to transition to an independent career in which she applies her engineering background to the study of microbial pathogenesis.

描述（由申请人提供）：放线菌聚集杆菌是一种革兰氏阴性病原体，是局部侵袭性牙周炎（LAP）和其他全身性感染（包括感染性心内膜炎）的病因。LAP影响着美国和全世界医疗服务不足的儿童，其特征是牙周韧带和牙槽骨结构的破坏，而牙周韧带和牙槽骨结构是固定牙齿的。如果不进行干预，牙齿就会脱落，造成外观畸形和功能缺陷。放线菌引起LAP的方式尚不清楚；然而，已知它会产生几种假定的毒力因子，包括白质毒素（LtxA），它是毒素重复片段（RTX）家族的一员。根据实验和临床数据，LtxA被认为是该细菌的主要毒力因子。因此，预防或干扰LtxA活性可能是治疗疾病的一种选择。这种毒素杀死人类和灵长类动物的白细胞，并可能在放线菌在感染期间逃避免疫反应中发挥作用。已经证明，在其与宿主细胞的初始反应中