Transforming Translational Science and Education to Benefit Human Health

转变转化科学和教育以造福人类健康

• 批准号: 8259883
• 负责人: Barry Coller
• 金额: $ 49.37万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259883
• 关键词: Adopted; Advocate; Affinity; Agar; Antibiotic Resistance; Antibiotics; Appearance; Applications Grants; Award; Bacteria; Biochemical; Biometry; Carbon; Cell Count; Cell Wall; Cells; Characteristics; Clinical; Clinical Protocols; Clinical Research; Clinical Sciences; Clinical and Translational Science Awards; Collaborations; Collection; Communities; Complement; Complex; DNA Sequencing Facility; Dendritic Cell Therapy; Development; Diagnosis; Discipline; Doctor of Philosophy; Epidemic; Faculty; Figs - dietary; Frequencies; Functional disorder; Genes; Genetic; Genetic Determinism; Genomics; Goals; Good Clinical Practice; Growth; HIV; Health; Hepatitis C; Heterogeneity; Home environment; Hospitals; Human; Human Resources; Immune response; Indium; Industry; Infection; Intermediate resistance; Intervention; Knowledge; Laboratories; Libraries; Life; Malignant Neoplasms; Medical; Metabolic; Metabolic Pathway; Methicillin; Methicillin Resistance; Methodology; Methods; Microbiology; Minority; Monobactams; Multi-Drug Resistance; Mutation; NCI Scholars Program; Names; Nature; New York; Nursing Research; Oxacillin; Participant; Pattern; Performance; Pharmacy facility; Phenotype; Population; Population Analysis; Prevention; Preventive; Property; Proteins; Recombinants; Research; Research Infrastructure; Research Personnel; Research Subjects; Resistance; Resistance profile; Resources; Running; Safety; Shapes; Site; Source; Specimen; Staphylococcus aureus; Structure; Techniques; Testing; Therapeutic; Time; Translational Research; Treatment Failure; U-Series Cooperative Agreements; United States National Institutes of Health; Universities; University Hospitals; Visit; Work; antimicrobial drug; bacterial resistance; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; biomedical informatics; clinical practice; genome sequencing; hazard; human disease; human subject protection; improved; innovation; medical schools; meetings; member; metabolomics; mutant; neglect; novel; novel diagnostics; novel strategies; programs; research study; resistance mechanism; resistant strain; science education; tool; trait; vaccine development

The Rockefeller University Hospital, a GCRC awardee since 1963, has been the continuous "home" for clinical and translational science at Rockefeller since 1910. It has been the site of numerous landmark scientific and clinical contributions, and many of its trainees have gone on to become academic leaders. With the new resources available under a Clinical and Translational Science Award (CTSA), a core faculty of. distinguished investigators, whose research spans the basic-translational spectrum and encompasses a broad range of scientific and medical disciplines, will integrate and expand their scientific and educational programs in a new Rockefeller University Center for Clinical and Translational Science. The new Center will transform clinical and translational research by encouraging new studies, and by enhancing and centralizing the support structures required to conduct studies with scientific rigor and an absolute commitment to protection of human subjects and participant safety. The key elements in the transformation will be: 1) A new governance structure reflecting the NIH cooperative agreement (U54) "assistance" mechanism, 2) Creation of a new K-12 Clinical Research Scholars Program offering Masters and PhD level degrees to complement the current Clinical Scholars Program, 3) Infrastructure enhancements to facilitate the development and conduct of clinical protocols under the principle of Good Clinical Practice (GCP), including biomedical informatics, biostatistics. bionutrition, research nursing, research pharmacy, participant recruitment and community engagement, and regulatory support and oversight from the clinical research (research subject advocate) support office, 4) Development of innovative and novel core methodologies related to dendritic cell therapy; vaccine development for HIV, hepatitis C, and malignancies; genetics/genomics; assessing the immune response; and metabolic phenotyping. The Center will continue Rockefeller's tradition of focusing on the interface between scientific discovery, human pathophysiology, and novel diagnostic, preventive and therapeutic strategies. It will partner with industry, when mutually beneficial, to achieve these goals. The Center will also be an active member of the National CTSA Consortium, offering the Consortium novel ideas and tools for conducting and evaluating clinical and translational research. It will also eagerly adopt the best practices identified by the Consortium and adhere to the standards set by the Consortium. Methillin resistant S. aureus (MRSA) was first identified in clinical specimen in 1961 - shortly after the introduction of the first beta-lactamase resistant antibiotic - Celbenin - into clinical practice. The key component of this resistance mechanism - the mecA gene - encoding a protein with very low affinity to all beta-lactam antibiotics - is not a native gene for S. aureus but has been acquired on multiple occasions from a "foreign" source in the form of chromosomal cassettes. MRSA clones have emerged as major causative agents of serious - and often life-threatening - infections in hospitals worldwide and beginning with the late 1990s MRSA also found its way into the community. The most widely spread epidemic clones of MRSA also acquired resistance traits to the great majority of antimicrobial agents and therapeutic options against such multidrug resistant strains have become reduced to less than a handful of agents. The primary motive of this grant proposal is to find novel intervention strategies against MRSA by exploring more closely the mechanism of beta-lactam resistance. Critical clues for such novel strategies were observations made in the two collaborating laboratories. The research program will use a combination of genetic, biochemical and metabolomic approaches and will be divided into four Specific Aims. Aim 1 will use metabolomic approaches to identify the mechanisms by which a library of auxiliary mutants can reduce resistance level of an MRSA strain. Aim 2 will compare the very different resistance levels produced by subpopulations of heterogeneously resistant epidemic clones of MRSA. Aim 3 will use genome sequencing to identify determinants in the genetic background of S. aureus that control the level of resistance to oxacillin. Aim 4 will use five contemporary isolates of MRSA recovered in Yr 2011 in New York hospital

洛克菲勒大学医院自 1963 年以来一直是 GCRC 获奖者，自 1910 年以来一直是洛克菲勒临床和转化科学的“家”。它是众多具有里程碑意义的科学和临床贡献的场所，许多受训者都继续在成为学术带头人。凭借临床和转化科学奖 (CTSA) 提供的新资源，核心教师。杰出的研究人员的研究跨越基础翻译领域，涵盖广泛的科学和医学学科，他们将在新的洛克菲勒大学临床和转化科学中心整合和扩展他们的科学和教育项目。新中心将通过鼓励新研究、加强和集中以科学严谨性和对保护人类受试者和参与者安全的绝对承诺进行研究所需的支持结构来改变临床和转化研究。转型的关键要素将是：1）反映 NIH 合作协议（U54）“援助”机制的新治理结构，2）创建新的 K-12 临床研究学者计划，提供硕士和博士学位，以补充当前的临床学者计划，3）增强基础设施，以促进根据良好临床实践（GCP）原则制定和实施临床方案，包括生物医学信息学、生物统计学。生物营养、研究护理、研究药学、参与者招募和社区参与以及临床研究（研究主题倡导者）支持办公室的监管支持和监督，4）开发与树突状细胞治疗相关的创新和新颖的核心方法；艾滋病毒、丙型肝炎和恶性肿瘤的疫苗开发；遗传学/基因组学；评估免疫反应；和代谢表型。该中心将延续洛克菲勒的传统，专注于科学发现、人类病理生理学以及新颖的诊断、预防和治疗策略之间的联系。它将与业界合作，在互惠互利的情况下实现这些目标。该中心还将成为国家 CTSA 联盟的积极成员，为联盟提供用于开展和评估临床和转化研究的新颖想法和工具。它还将积极采用联盟确定的最佳实践，并遵守联盟制定的标准。 耐甲氧西林金黄色葡萄球菌 (MRSA) 于 1961 年首次在临床样本中被鉴定出来，即在第一种耐 β-内酰胺酶抗生素 - Celbenin 引入临床实践后不久。这种耐药机制的关键组成部分 - mecA 基因 - 编码一种对所有 β-内酰胺抗生素亲和力极低的蛋白质 - 不是金黄色葡萄球菌的天然基因，而是多次从“外国”来源获得的染色体盒的形式。 MRSA 克隆已成为世界各地医院中严重且常常危及生命的感染的主要病原体，并且从 20 世纪 90 年代末开始，MRSA 也进入了社区。 MRSA 传播最广泛的流行性克隆也获得了对绝大多数抗菌药物的耐药性特征，针对此类多重耐药菌株的治疗选择已减少到不到几种。 这项拨款提案的主要动机是通过更仔细地探索 β-内酰胺耐药机制来寻找针对 MRSA 的新干预策略。这种新颖策略的关键线索是在两个合作实验室中进行的观察。 该研究计划将结合遗传、生化和代谢组学方法，分为四个具体目标。 目标 1 将使用代谢组学方法来确定辅助突变体库降低 MRSA 菌株耐药水平的机制。 目标 2 将比较 MRSA 异质耐药流行性克隆亚群产生的截然不同的耐药水平。 目标 3 将利用基因组测序来识别金黄色葡萄球菌遗传背景中控制苯唑西林耐药水平的决定因素。 目标 4 将使用 2011 年在纽约医院发现的 5 种当代 MRSA 分离株