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.

新英格兰地区的生物化和新兴传染病卓越中心（NERCE） 现在已经活跃了五年。台球最初设定了已经实现的几个目标 重要程度。这些目标是将现有科学信息转化为可部署技术， 使我们社区的科学创造力持续开发新颖的治疗方法和 预防感染，并为科学家和医生提供生物幻想和医生的培训机会 新兴的传染病。我们想创建一个中心，该中心是研究的焦点和 学术界的科学家将利用生物幻想和新兴传染病的发展 公共卫生部门以及药物和生物技术行业。我们的目的是这个中心 将充当基本，转化和临床研究科学家进行研究领先的催化剂 针对针对传染性药物的新产品。 最初五年的统计数据为我们成功实现这些目标提供了成功的证据。我们已经资助了 来自新英格兰15个机构的65名调查员，其中大多数没有事先工作的经验 与生物固定病原体。已提交了14项专利，并于 Nerce提供的支持。此外，尼尔的主要功能是建立核心设施 为整个地区的调查人员（包括未直接由Nerce资助的研究人员）提供研究 基本机构无法提供所需的基础设施来与这些病原体一起使用。我们的核心实验室 不仅是来自我们地区的150位科学家，而且还来自美国的其他所有RCE。 我们的国家小分子筛选核心（NSRB）与70多名调查员合作（一半来自 在我们区域之外）进行高通量小分子筛选，以抑制特异性的化合物 分子或感兴趣的生物学途径。 NSRB一直是Transcenter Core中最成功的 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，已提供给参与调查人员的图书馆，我们提供了合作 作为我们的药物化学计划的一部分，拥有超过400个定制合成化合物的科学家。我们的BSL3 实验室是由尼尔独立开发的，使用哈佛医学院提供的资金。这 实验室已在CDC注册以使用高度调节的精选代理，是新的少数 英格兰向我们地区的调查员开放，希望与生物植物病原体合作。都合作 在BSL3中工作的调查人员接受了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 Biomoletecule生产核心已协助调查人员 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，导致44 kg细菌细胞糊。最后，我们的蛋白质组学核心 实验室已经为Francisella Tularensis和Yersinia Pestis准备了克隆的Orfeome库，最初 新英格兰调查人员的支持，随后为全国的科学家提供了支持。 我们的研究计划为调查人员提供了四种类型的财政支持，包括：1）研究 项目，2）发展项目，3）职业发展奖学金和4）通过RCE的资金 机会“计划。我们资助了17个主要研究项目，16个发展项目，7个职业 开发奖和14个其他项目通过新机会。我们的研究一直集中在 围绕宿主 - 病原体相互作用和细菌毒素的主题，我们建议继续进行主题 接下来的五年。我们有针对理解先天和适应性机制的计划 对重要病原体的免疫力，基于从中获得的理解来开发治疗剂和疫苗 研究宿主病原体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和杀死宿主细胞。 成功开发研究计划的一个很好的例子，该计划可能会导致重要的治疗 干预是詹姆斯·坎宁安（James Cunningham）领导的研究计划，詹姆斯·坎宁安（James Cunningham 妇女医院。坎宁安实验室的博士后研究员Kartik Chandran博士被授予了一个核 职业发展奖学金，以支持对埃博拉病毒进入宿主细胞的机制的研究。 这项工作发现，在组织蛋白酶家族中，宿主蛋白酶对病毒糖蛋白的切割至关重要 病毒进入的早期阶段。钱德兰和坎宁安发现，入侵过程被打断了 用各种小分子组织蛋白酶抑制剂抑制这种裂解。此外，钱德兰 坎宁安不仅通过伪型病毒记者系统展示了这一点，而且还通过致病性展示了这一点 埃博拉病毒是与Usamriid科学家合作的一部分。坎宁安博士最近有 开始专注于组织蛋白酶抑制剂，该抑制剂也在临床上作为癌症治疗。一起 在NSRB筛查核心和动物模型专家的医疗化学家与BSL3相关 核心，已经准备了大量候选治疗性，并初始生物利用度和给药 已经进行了研究，以准备在豚鼠和灵长类动物中进行挑战研究。后者的工作 最初是由Nerce Development项目奖的支持，现在是主要研究项目。 坎宁安项目通过多种方式实现了尼尔的目标。它是作为一个基本调查 并提高到可能为临床前翻译工作做好准备的地步，以此作为确定的一部分 目前尚无治疗的感染治疗剂。它也有潜力 基本发现如何导致对侵入多种代理的广泛方法的模型 宿主细胞通过相似的机制。 实现预防干预措施的一个例子是丹尼斯·卡斯珀（Dennis Kasper）实验室的工作 tularemia疫苗。该项目的一部分开始是对参与生物合成基因的基本研究 Francisella tularensis的脂多糖（LPS）的O多糖成分。重要 卡斯珀实验室（Kasper Lab）提出的发现是O多糖在F. tularensis毒力中具有关键作用。 具体而言，他们发现使用0多糖生物合成基因（WBTA，脱氢酶）的破坏 插入诱变降低了Tularensis的LVS菌株的毒力，LD50在实验室动物中 从101增加到107cfu。毒力的降低归因于突变体对 血清和补体的杀菌作用。这种观察结果促进了使用衰减的研究 突变体是一种潜在的疫苗，可针对这种细胞内病原体诱导细胞免疫。但是，也是如此 显而易见的是，O多糖抗体在保护性免疫中起着重要作用，导致 使用WBTA突变体的组合疫苗和O的糖缀合物的其他研究 多糖与破伤风毒素结合。实验动物疫苗 /挑战研究的结果是 非常令人鼓舞。这种组合疫苗是最早显示保护性的疫苗之一 反对野生型A和B菌株的挑战。 这些F. tularensis疫苗研究可能具有广泛的适用性。所有革兰氏阴性细菌均具有LP，并且 这种方法可能是针对其他生物开发疫苗的重要模型。这个项目有 利用了尼尔的几乎每个核心实验室，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，表明研究之间的富有成效关系 核心实验室中的科学家和科学家可以带来重大的科学成就。