Administrative Diversity Supplement for Aimee Potter

艾米·波特的行政多元化补充

基本信息

批准号：
10818164
负责人：
CYNTHIA N CORNELISSEN
金额：
$ 13.7万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-09 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10818164
关键词：
Affect Affinity Algorithms Animals Antibiotic Resistance Antibiotics Award Bacteria Binding Binding Proteins Biochemical Biochemical Pathway Biological Assay Biological Availability Biology Centers for Disease Control and Prevention (U.S.)Chemicals Complement Complex Data Data Set Dependence Energy Supply Enterobactin Environment Enzyme-Linked Immunosorbent Assay Epithelium Erythrocytes Exposure to Future Genes Genetic Genetic Transcription Goals Gonorrhea Gram-Negative Bacteria Growth Hemoglobin Human Immune system Incidence Infection Inflammatory Response Interdisciplinary Study Investigation Iron Iron-Binding Proteins Lactoferrin Leukocyte L1 Antigen Complex Ligand Binding Ligands Lipoproteins Measures Membrane Metabolic Pathway Metabolism Metals Modeling Mucous Membrane Neisseria gonorrhoeae Neutrophil Infiltration Nutritional Nutritional Immunity Nutritional Requirements Parents Pathogenesis Pharyngeal structure Phenotype Postdoctoral Fellow Primates Principal Investigator Proteins Proton-Motive Force Public Health Rectum Research Resistance Role Serum Sexually Transmitted Diseases Siderophores Site Source Superbug Surface System Testing Time Training Transferrin World Health Organization Zinc antimicrobial bacterial genetics career chemokine combat conjunctiva drug-resistant gonorrhea gene product genetic manipulation genome-wide insight interest lactoferrin receptors member microbiota mutant neutrophil novel strategies novel therapeutics pathogen prototype psoriasin receptor reconstruction rectal response skills tenure track transcriptome transcriptome sequencing urogenital tract

项目摘要

PROJECT SUMMARY/ABSTRACT Neisseria gonorrhoeae (Ngo) is the bacterium that causes the sexually transmitted infection gonorrhea. Infection with Ngo triggers a potent inflammatory response at mucosal epithelial surfaces that is characterized by recruitment of neutrophils, which are unable to clear the bacteria. With mounting antibiotic resistance in Ngo, new therapeutics are urgently needed to treat gonorrhea, and one promising approach is to combat its dependence on metals such as iron and zinc that are acquired from its obligate human host. In humans and other mammalian hosts, essential metals are found within high affinity complexes with proteins and are not freely available. Examples of these proteins are the iron-binding transferrin and hemoglobin, found in abundance in serum/erythrocytes, and zinc-binding lactoferrin and calprotectin, which are found in abundance in neutrophils as well as mucosal secretions. To overcome this restriction (“nutritional immunity”), Ngo produces outer-membrane, surface-exposed transporters that bind to human metal-binding proteins and extract the metal from them directly, via energy supplied by the TonB system. There are 8 known TonB- dependent transporters (Tdts) in Ngo. Four Tdts are the focus of the parent application: TdfH and TdfJ, which bind to human calprotectin and psoriasin, respectively, to acquire zinc; and TdfF and TdfG, which are iron- regulated but whose ligands and functions remain undefined. Four other Tdts are involved in metal acquisition in Ngo: TbpA, which binds human transferrin; LbpA, which binds human lactoferrin; HpuB, which binds human hemoglobin; and FetA, which binds ferric enterobactin, a siderophore produced by members of the microbiota. In this diversity supplement application, we propose three Specific Aims that are independent of the parent R01 award: 1) Test the role for TbpAB, FetAB, and HpuAB in survival and outgrowth of Ngo exposed to primary human neutrophils, including the necessity for ligand binding and TonB-dependent transport; 2) Determine the bioavailable metals and their cognate metal-binding proteins that are available to Ngo during infection of neutrophils; and 3) Define the metabolic pathways Ngo differentially uses in metal-depleted and metal-replete growth conditions. The latter Aim will leverage a recent genome-scale metabolic network reconstruction our lab recently created, contextualized with publicly available metal-dependent transcriptional datasets of Ngo. Completion of these Aims will reveal new insights into the response of Ngo to human nutritional immunity and uncover new biology for future mechanistic investigation at this host-pathogen interface. It will provide the diversity supplement postdoctoral trainee with defined training in bacterial genetic manipulation and neutrophil functional assays, while engaging the trainee in the interdisciplinary research taking place under the auspices of the parent R01. At the same time, the trainee will develop career transitional skills and uncover new research foci, which will help her achieve her career goal of becoming an independent tenure-track principal investigator in Ngo biology and pathogenesis.

项目摘要/摘要 Neisseria Gonorrhoeae（NGO）是导致性传播感染淋病的细菌。非政府组织的感染会触发粘膜上皮表面的潜在炎症反应通过募集无法清除细菌的中性粒细胞。具有安装抗生素的抗性非政府组织，迫切需要新的治疗剂来治疗淋病，一种有前途的方法是打击依赖于从其专有人类宿主那里获得的铁和锌等金属。在人类和其他哺乳动物宿主，在具有蛋白质的高亲和力络合物中发现必需的金属，而不是免费提供。这些蛋白质的例子是在血清/红细胞的抽象以及锌结合乳铁蛋白和钙染色蛋白，在抽象中发现在中性粒细胞和粘膜分泌物中。为了克服这种限制（“营养免疫”），非政府组织产生外膜，表面暴露的转运蛋白，该转运蛋白与人金属结合蛋白结合和直接通过TONB系统提供的能量直接从中提取金属。有8个已知的tonb- 非政府组织中的依赖转运蛋白（TDTS）。四个TDT是父申请的重点：TDFH和TDFJ，其中分别与人钙卫蛋白和牛皮癣结合，以获取锌；以及TDFF和TDFG，是铁 - 受监管，但其配体和功能仍然不确定。其他四个TDT也参与了金属采集在非政府组织：结合人类转铁蛋白的TBPA中； LBPA，结合人乳铁蛋白； HPUB，结合人血红蛋白；和羊乳突，它结合了铁肠乳蛋白，这是由微生物群成员产生的铁载体。在这种多样性补充应用中，我们提出了独立于父母的三个特定目标 R01奖：1）测试tbpab，fetab和hpuab在暴露于非政府组织的生存和生存中的作用原代人性嗜中性粒细胞，包括配体结合和依赖TONB的运输所必需的； 2）确定可用于非政府组织的生物利用金属及其同源金属结合蛋白中性粒细胞的感染； 3）定义代谢途径在金属耗尽和金属恢复生长条件。后一个目标将利用最近的基因组规模代谢网络重建我们的实验室最近创建的，与公开可用的金属转录相关化非政府组织的数据集。这些目标的完成将揭示对非政府组织对人类反应的新见解营养免疫力并发现该宿主病原体未来机械投资的新生物学界面。它将为多样性补充博士学员提供细菌通用培训的定义培训操纵和中性粒细胞功能分析，同时让学员参与跨学科研究发生在父母R01的主持下。同时，学员将发展职业过渡技能和发现新的研究重点，这将有助于她实现成为独立的职业目标非政府组织生物学和发病机理的终身轨道主要研究者。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stealthy microbes: How Neisseria gonorrhoeae hijacks bulwarked iron during infection.

DOI：
10.3389/fcimb.2022.1017348
发表时间：
2022
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
通讯作者：

Mutagenesis of the Loop 3 α-Helix of Neisseria gonorrhoeae TdfJ Inhibits S100A7 Binding and Utilization.

DOI：
10.1128/mbio.01670-22
发表时间：
2022-08-30
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Transcriptional activation of ompA in Neisseria gonorrhoeae mediated by the XRE family member protein NceR.

DOI：
10.1128/mbio.01244-23
发表时间：
2023-08-31
期刊：
MBIO
影响因子：
6.4
作者：
Holley, Concerta L. L.;Dhulipala, Vijaya;Maurakis, Stavaros A. A.;Greenawalt, Ashley Nicole;Read, Timothy D. D.;Cornelissen, Cynthia N. N.;Shafer, William M. M.
通讯作者：
Shafer, William M. M.

Point Mutations in TbpA Abrogate Human Transferrin Binding in Neisseria gonorrhoeae