Administrative Core

行政核心

• 批准号: 8233430
• 负责人: Dennis L. Kasper
• 金额: $ 75.56万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233430
• 关键词: Academia; Address; Anabolism; Animal Model; Antibodies; Attenuated; Award; Bacteria; Bacterial Toxins; Base Sequence; Basic Science; Biological; Biological Availability; Biotechnology; Carbohydrates; Cathepsins; Cavia; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Clinical Research; Collaborations; Combined Vaccines; Communicable Diseases; Communities; Complement; Containment; Core Facility; Country; Coupled; Creativeness; Custom; Databases; Development; Dose; Ebola virus; Emerging Communicable Diseases; Ensure; Epidemiology; Equipment; Family; Federal Government; Fellowship; Fermentation; Financial Support; Francisella tularensis; Funding; Genes; Glycoconjugates; Glycoproteins; Goals; Government; Gram-Negative Bacteria; Hospitals; Hydro-Lyases; Immunity; Industry; Infection; Infection prevention; Infectious Agent; Insertional Mutagenesis; Institution; Invaded; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Animals; Lead; Legal patent; Lethal Dose 50; Libraries; Lipopolysaccharides; Malignant Neoplasms; Manuscripts; Mass Spectrum Analysis; Microscopy; Modeling; Natural Immunity; New England; Nucleic acid sequencing; Organism; Paste substance; Pathogenesis; Pathway interactions; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmacologic Substance; Physicians; Play; Polysaccharides; Postdoctoral Fellow; Preparation; Preventive Intervention; Primates; Process; Production; Proteomics; Public Health; Publishing; RNA Interference; Recombinant Proteins; Reporter; Research; Research Infrastructure; Research Personnel; Research Project Grants; Risk; Role; Safety; Scientific Advances and Accomplishments; Scientist; Screening procedure; Serum; Specialist; Staging; Strategic Planning; System; Technology; Tetanus Toxoid; Therapeutic; Therapeutic Intervention; Toxin; Training; Training Programs; Translating; Translational Research; Tularemia; Update; Ursidae Family; Vaccines; Viral; Virulence; Virus; Woman; Work; Yersinia pestis; adaptive immunity; animal model development; bactericide; base; biodefense; career development; catalyst; experience; human disease; inhibitor/antagonist; interest; killings; medical schools; molecular imaging; mutant; novel strategies; pathogen; pre-clinical; programs; research and development; small molecule; statistics; success; therapeutic target; therapeutic vaccine; tool; vaccine candidate; vaccine development

The New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (NERCE) has now been active for over five years. NERCE originally set several goals that have been achieved to a significant degree. These goals were to translate existing scientific information into deployable technology, to bring the scientific creativity of our community to bear on developing novel approaches to treatment and prevention of infections, and to provide training opportunities for scientists and physicians in biodefense and emerging infectious diseases. We wanted to create a center that served as a focal point for research and development in biodefense and emerging infectious diseases to be utilized by scientists from academia, the public health sector, and the pharmaceutical and biotechnology industries. Our intent was that this center would function as a catalyst for basic, translational, and clinical research scientists to conduct research leading to new products directed against infectious agents. Statistics from the first five years provide evidence of our success in achieving these goals. We have funded 65 investigators from 15 institutions throughout New England, most of whom had no prior experience working with biodefense pathogens. Fourteen patents have been filed and 101 manuscripts published as a result of support provided by NERCE. In addition, a major function of NERCE has been to establish core facilities to enable research for investigators throughout the region (including those not directly funded by NERCE) whose base institutions cannot provide the required infrastructure to work with these pathogens. Our core laboratories have been utilized by 150 scientists, not only from our region but also from nearly every other RCE in the US. Our National Small Molecule Screening Core (NSRB) has collaborated with over 70 investigators (half from outside our region) in conducting high-throughput small molecule screens for compounds that inhibit specific molecules or biological pathways of interest. The NSRB has been the most successful of the transcenter core laboratories supported by the RCE program. We have developed extensive synthetic and natural compound libraries, which have been made available to participating investigators, and we have provided collaborating scientists with over 400 custom-synthesized compounds as part of our medicinal chemistry program. Our BSL3 laboratory was independently developed by NERCE using funds provided by Harvard Medical School. The laboratory is registered with the CDC for use of highly regulated select agents and is one of the few in New England open to investigators from our region wishing to work with biodefense pathogens. All collaborating investigators working in the BSL3 undergo a rigorous biosafety training program to ensure safety of laboratory workers and others in the community. The NERCE Biomolecule Production Core has assisted investigators with the production of over 100 different recombinant proteins and carbohydrate preparations; this core has conducted nearly 300 fermentations, resulting in 44 kg of bacterial cell paste. Finally, our proteomics core laboratory has prepared cloned orfeome libraries for both Francisella tularensis and Yersinia pestis, initially in support of New England investigators and subsequently for scientists across the country. Our research program has offered four types of financial support for investigators, including: 1) research projects, 2) developmental projects, 3) career development fellowships, and 4) funding through the RCE "New Opportunities" program. We have funded 17 major research projects, 16 Developmental Projects, 7 Career Development Awards, and 14 additional projects through New Opportunities. Our research has been focused around the themes of host-pathogen interactions and bacterial toxins, themes that we propose to continue over the next five years. We have programs targeted at understanding the mechanisms of innate and adaptive immunity to important pathogens, developing therapeutics and vaccines based on understanding gained from investigating host-pathogen interactions and studying how bacteria and viruses circumvent normal defenses, and understanding how toxins enter and kill host cells. A good example of successful development of a research program that may lead to an important therapeutic intervention is the research program led by James Cunningham, a NERCE investigator based at Brigham and Women's Hospital. Dr. Kartik Chandran, a postdoctoral fellow in the Cunningham lab, was awarded a NERCE Career Development fellowship to support studies of the mechanism by which Ebola virus enters the host cell. This work found that cleavage of the viral glycoprotein by a host protease in the cathepsin family is essential in the early stages of viral entry. Chandran and Cunningham found that the invasive process was interrupted by inhibiting this cleavage with any of a variety of small molecule cathepsin inhibitors. Furthermore, Chandran and Cunningham showed this not only with pseudotyped virus reporter systems, but also with pathogenic Ebola virus as part of a collaboration with scientists from USAMRIID. Dr. Cunningham has more recently begun to focus on a cathepsin inhibitor that is also being studied clinically as a cancer therapeutic. Together with medicinal chemists at the NSRB screening core and animal model specialists affiliated with the BSL3 core, large quantities of the candidate therapeutic have been prepared, and initial bioavailability and dosing studies have been conducted in preparation for challenge studies in guinea pigs and primates. This latter work was supported initially by a NERCE Developmental Projects award and now as a primary research project. The Cunningham project has fulfilled the goals of NERCE in several ways. It began as a basic investigation and advanced to the point where it may be ready for preclinical translational work as part of an effort to identify therapeutics for an infection for which there are no therapies currently available. It also serves as a potential model for how basic discovery could lead to broad-spectrum approaches against multiple agents that invade host cells though similar mechanisms. An example of achieving possible preventive interventions is the work of Dennis Kasper's laboratory on tularemia vaccines. One portion of this project started as a basic study of genes involved in the biosynthesis of the O polysaccharide component of the lipopolysaccharide (LPS) of Francisella tularensis. The important discovery made by the Kasper lab was that the O polysaccharide has a critical role in F. tularensis virulence. Specifically, they found that disruption of an 0 polysaccharide biosynthetic gene (wbtA, a dehydratase) using insertional mutagenesis reduced virulence of the LVS strain of tularensis, with the LD50 in laboratory animals increasing from 101 to 107cfu. The reduction in virulence is attributed to the mutant's increased sensitivity to the bactericidal effects of serum and complement. This observation provoked studies using the attenuated mutant as a potential vaccine to induce cellular immunity against this intracellular pathogen. However, it also became apparent that antibody to O polysaccharide played an important role in protective immunity, leading to additional studies using a combination vaccine of the wbtA mutant plus a glycoconjugate of the O polysaccharide coupled to tetanus toxoid. The results of vaccine / challenge studies in laboratory animals are very encouraging. This combination vaccine is one of the first vaccine candidates shown to be protective against challenge with both wild-type A and B strains of F. tularensis. These F. tularensis vaccine studies could have broad applicability. All gram negative bacteria have LPS, and this approach might be an important model for developing vaccines against other organisms. This project has utilized nearly every core lab in NERCE, including the proteomics core, the small molecule screening core, the biomolecule production core, and the BSL3 core, illustrating that a productive relationship between research scientists and scientists in the core labs can lead to significant scientific accomplishments.

新英格兰地区生物防御和新发传染病卓越中心 (NERCE) 现已活跃五年多。 NERCE 最初设定了几个目标，这些目标已经实现 显着程度。这些目标是将现有的科学信息转化为可部署的技术， 将我们社区的科学创造力用于开发新的治疗方法和 预防感染，并为科学家和医生提供生物防御和 新出现的传染病。我们想创建一个中心作为研究和研究的焦点 生物防御和新出现的传染病的发展将被学术界、 公共卫生部门以及制药和生物技术行业。我们的目的是让这个中心 将充当基础、转化和临床研究科学家开展研究领先的催化剂 针对传染性病原体的新产品。 前五年的统计数据证明我们成功实现了这些目标。我们已资助 来自新英格兰 15 个机构的 65 名调查员，其中大多数人之前没有工作经验 与生物防御病原体。已申请专利 14 项，发表论文 101 篇 由 NERCE 提供支持。此外，NERCE的一个主要职能是建立核心设施 为整个地区的研究人员（包括那些不直接由 NERCE 资助的研究人员）提供研究支持 基地机构无法提供处理这些病原体所需的基础设施。我们的核心实验室 已被 150 名科学家使用，他们不仅来自我们地区，还来自美国几乎所有其他 RCE。 我们的国家小分子筛选核心 (NSRB) 已与 70 多名研究人员合作（一半来自 我们区域之外）进行高通量小分子筛选，寻找抑制特定化合物的化合物 感兴趣的分子或生物途径。 NSRB 是最成功的跨中心核心 RCE 计划支持的实验室。我们开发了广泛的合成和天然化合物 图书馆，已向参与研究人员开放，并且我们提供了合作 作为我们药物化学项目的一部分，科学家们拥有 400 多种定制合成的化合物。我们的 BSL3 实验室是NERCE利用哈佛医学院提供的资金独立开发的。这 该实验室已在美国疾病控制与预防中心 (CDC) 注册，可使用受到严格监管的精选药物，并且是新州为数不多的实验室之一。 英格兰向我们地区希望研究生物防御病原体的研究人员开放。全体协作 在 BSL3 工作的研究人员接受严格的生物安全培训计划，以确保实验室的安全 工人和社区中的其他人。 NERCE 生物分子生产核心协助研究人员 生产 100 多种不同的重组蛋白和碳水化合物制剂；这个核心有 进行了近300次发酵，产生了44公斤细菌细胞糊。最后，我们的蛋白质组学核心 实验室已为土拉弗朗西斯菌和鼠疫耶尔森氏菌制备了克隆的 orfeome 文库，最初于 支持新英格兰研究人员以及随后全国各地科学家的支持。 我们的研究计划为研究人员提供了四种类型的财务支持，包括：1）研究 项目，2) 发展项目，3) 职业发展奖学金，以及 4) 通过 RCE“新 机会”计划。我们资助了 17 个重大研究项目、16 个发展项目、7 个职业项目 发展奖，以及通过新机会获得的 14 个其他项目。我们的研究重点 围绕宿主-病原体相互作用和细菌毒素的主题，我们建议继续讨论这些主题 未来五年。我们有旨在了解先天和适应性机制的计划 对重要病原体的免疫力，根据获得的了解开发治疗方法和疫苗 研究宿主与病原体的相互作用并研究细菌和病毒如何规避正常防御， 并了解毒素如何进入并杀死宿主细胞。 成功开发研究项目的一个很好的例子，该项目可能会带来重要的治疗方法 干预是由詹姆斯·坎宁安 (James Cunningham) 领导的一项研究项目，詹姆斯·坎宁安 (James Cunningham) 是布里格姆大学的 NERCE 研究员。 妇女医院。 Cunningham 实验室博士后 Kartik Chandran 博士荣获 NERCE 职业发展奖学金支持埃博拉病毒进入宿主细胞机制的研究。 这项工作发现组织蛋白酶家族中的宿主蛋白酶对病毒糖蛋白的裂解对于 病毒进入的早期阶段。钱德兰和坎宁安发现侵入过程被中断 使用多种小分子组织蛋白酶抑制剂中的任何一种来抑制这种裂解。此外，钱德兰 坎宁安不仅通过假型病毒报告系统证明了这一点，还通过致病性证明了这一点 埃博拉病毒是与 USAMRIID 科学家合作的一部分。坎宁安博士最近 开始关注组织蛋白酶抑制剂，该抑制剂也正在作为癌症治疗剂进行临床研究。一起 与 NSRB 筛选核心的药物化学家和 BSL3 附属的动物模型专家合作 核心，已制备大量候选治疗剂，以及初始生物利用度和剂量 已经进行了一些研究，为豚鼠和灵长类动物的挑战研究做准备。后者的作品 最初由 NERCE 发展项目奖支持，现在作为主要研究项目。 Cunningham 项目在多个方面实现了 NERCE 的目标。一开始是一项基本调查 并进展到可以为临床前转化工作做好准备，作为确定的努力的一部分 针对目前尚无可用疗法的感染的治疗方法。它也可以作为一个潜在的 基本发现如何导致针对多种入侵代理的广谱方法的模型 宿主细胞通过类似的机制。 实现可能的预防性干预措施的一个例子是丹尼斯·卡斯珀实验室的工作 兔热病疫苗。该项目的一部分始于对参与生物合成的基因的基础研究。 土拉弗朗西斯菌脂多糖 (LPS) 的 O 多糖成分。重要的 Kasper 实验室的发现是 O 多糖在土拉弗拉菌毒力中发挥着关键作用。 具体来说，他们发现使用 0 多糖生物合成基因（wbtA，一种脱水酶）的破坏 插入诱变降低了土拉菌 LVS 菌株的毒力，实验动物中的 LD50 从 101cfu 增加到 107cfu。毒力的降低归因于突变体对病毒的敏感性增加 血清和补体的杀菌作用。这一观察结果引发了使用减毒的研究 突变体作为潜在的疫苗来诱导针对这种细胞内病原体的细胞免疫。然而，它也 显而易见，O 多糖抗体在保护性免疫中发挥着重要作用，导致 使用 wbtA 突变体和 O 糖复合物的组合疫苗进行了其他研究 与破伤风类毒素偶联的多糖。实验动物疫苗/攻击研究的结果是 非常令人鼓舞。这种组合疫苗是首批被证明具有保护作用的候选疫苗之一 对抗土拉弗朗西斯野生型 A 和 B 菌株的攻击。 这些土拉弗朗西斯菌疫苗研究可能具有广泛的适用性。所有革兰氏阴性细菌都含有脂多糖，并且 这种方法可能是开发针对其他生物体的疫苗的重要模型。该项目有 几乎利用了 NERCE 的所有核心实验室，包括蛋白质组学核心、小分子筛选核心、 生物分子生产核心和 BSL3 核心，说明研究之间的生产关系 核心实验室的科学家和科学家可以取得重大的科学成就。