Chemistry Core

化学核心

• 批准号: 7490274
• 负责人: Wellington Pham
• 金额: $ 12.53万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490274
• 关键词: Achievement; Address; Aleurites; Amendment; Apoptosis; Area; Budgets; Businesses; Chemistry; Commercial Sources; Contrast Media; Development; Drug Delivery Systems; Dyes; Epidermal Growth Factor Receptor; Equipment; Equipment and Supplies; Exclusion; Faculty; Feedback; Fees; Fluorescence Resonance Energy Transfer; Funding; Heart; Housing; Human Resources; Image; Individual; Investments; Laboratories; Ligands; Link; Malignant Neoplasms; Matrilysin; Matrix Metalloproteinases; Measures; Metals; Methods; Minor; Modality; Modeling; Modification; Molecular Probes; Molecular Target; Molting; Monitor; New Agents; Nuclear; Numbers; Optics; PTGS2 gene; Peptides; Phage Display; Physiological; Physiology; Postdoctoral Fellow; Production; Publications; Published Comment; Publishing; Radiochemistry; Reading; Reagent; Reporter; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Role; Services; Source; Staging; Structure; Synthesis Chemistry; Therapeutic Intervention; Time; Training; Tumor Burden; Work; Writing; annexin A5; base; chemotherapy; cost; design; experience; imaging probe; in vivo Cellular and Molecular Imaging Centers; innovation; iron oxide; knowledge base; medical schools; molecular imaging; novel; programs; receptor expression; recombinant peptide; research and development; response; tumor

INTRODUCTION TO THE REVISED PROPOSAL This is a first revision of the proposed ICMIC Specialized Resource B, the Chemistry Core. The applicants thank the review panel for their numerous positive comments and constructive feedback regarding the previous submission. Clearly the reviewers appreciated the value of the Core and the advantages of supporting personnel and resources dedicated to the development and provision of optical and MR agents for the programs of the ICMIC. However, the reviewers also had some concerns about the organization of the Core and felt some aspects were not clearly described. In this revision, we have addressed all of the major and minor concerns from the previous review and have added a substantial quantity of new, relevant information regarding the capability and structure of our proposed Core. The Core personnel remain unchanged from the previous submission, and in the past year they have worked together to commission new chemistry laboratories that would be the heart of the proposed Core. Below, we discuss in detail the most significant concerns raised in the review and summarize our response. "Unfortunately, this Core write up focuses on equipment and preliminary work linked to the four Research Projects, rather than a more comprehensive glimpse at capabilities. There is little to no discussion of fee structure and business model." The revised Core description has been changed to provide more of an overview of our capabilities, and some of these are best illustrated by closely examining recent achievements relevant to specific projects. We also now include a more complete financial plan and we have clarified the costs associated with probe production. In general the priorities of the Core will be set by the Core staff with guidance from the Executive Steering Committee. The individual projects differ in their needs. We have attempted to distinguish between the provision of probes that have already been developed to a stage of some maturity (and which can be provided "on demand" for nominal costs), and those that involve more innovation and exploratory chemistry (and which require more original research and development). The supply budget of the Core has been increased to more fully cover the costs of these needs. We hope the revised write-up adequately describes our overall capability, and in addition shows how the individual projects will be facilitated. "The Chemistry Core concentrates on the development of new optical agents. A number of optical agents are already routinely available through this Core and the synthesis of newer agents appears well within the scope of the present work. While MR agents are described in Research Project 4, their synthesis is. not adequately described in the Core" Our exclusion of a description of the MR probe capability within the context of the Chemistry Core was an oversight in the previous submission. In addition, at that time we envisioned obtaining the novel proteolytic MR agent of Project 4 from an industrial source. We now include in section [6] the synthesis of DOTA-peptide probes and the development of MR agents sensitive to the effects of MMPs. It is noteworthy that our chemistry team has extensive experience on the design, synthesis and modification of MR molecular imaging agents. Dr. Don Molting has been formally trained in the design of metal chelates as MR contrast agents, while Drs Pham, Bornhop, and Manning have many publications in this area (see investigator bio-sketches). In addition, Dr. Pham has worked extensively on the design and development of iron oxide agents for MR contrast. The Core priorities will be determined by the needs of the projects and overall there is a greater emphasis on new optical and nuclear agents than on new MR agents. "One issue in the Core budget is that Dr. Manning is also on Research Project 1 and Dr. Pham is on Research Project 4. It is not clear how their time will be divided and billed.'" The apportionment of effort in both the Chemistry Core and Research Projects 1 and 4 does not reflect duplication of effort on the part of Drs. Manning and Pham. Within Projects 1 and 4 their efforts will be focused on particular innovative developments and exploratory chemistry that are specific to those projects. Their allocation of effort to those projects reflects their investment in the original intellectual ideas of those programs. In addition, however, they each will have more general responsibility for meeting the needs of other projects and for providing, via the Core, agents that have advanced to a more mature stage. We could have elected to put all their efforts into the Core but feel allocating some of their time to specific projects more properly reflects their close involvement with those research programs. Overall, we feel their total effort is reasonable given the scope of work proposed. "One weakness is that it is somewhat disingenuous to present the work described in Section b (Design of a NIR acceptor quencher) of "Proposed Novel Synthetic Chemistry" as new and exploratory since it had already been published in 2002 by the Core Director and his advisors while he was a postdoctoral fellow with Dr. Tung at Harvard Medical School.'" In our last submission, we did not adequately communicate that the synthetic work regarding the modification of NIRQ750 was a technical amendment to an established method that the Core Director developed in the past (Pham et al. Angew. Chem. Int. Ed. 2002, 41, 3659-62). We agree that overall this work is not technically novel, and we have now included this agent as an established probe that will be available.

修订提案简介这是对拟议的ICMIC专业版的第一次修订 资源B，化学核心。申请者感谢审查小组提出的许多积极的意见。 以及对上一次提交的意见的建设性反馈。显然，评论家们认识到了 核心和优势支撑人员和资源致力于发展和 为ICMIC的项目提供光学和磁共振代理。然而，评论家们也有一些 对核心组织的关切，并认为有些方面没有清楚说明。在这次修订中， 我们已经解决了上次审查中的所有主要和次要问题，并增加了大量 关于我们建议的核心的能力和结构的新的相关信息的数量。《核心》 工作人员与上次提交的文件保持不变，在过去的一年里，他们共同努力 委托新的化学实验室，这将是拟议的核心。下面，我们将在 详细说明审查中提出的最重要的关切，并总结我们的回应。 不幸的是，这份核心报告的重点是与四项研究相关的设备和前期工作 项目，而不是更全面地一瞥功能。很少或根本没有关于费用的讨论。 结构和商业模式。 修订后的核心描述已更改，以提供对我们能力的更多概述，以及 其中一些是通过仔细研究与具体项目相关的最新成就来最好地说明的。我们 现在还包括更完整的财务计划，我们已经澄清了与调查相关的成本 制作。一般而言，核心的优先事项将由核心工作人员在执行人员的指导下确定 督导委员会。各个项目的需求各不相同。我们已经尝试区分 提供已经发展到一定成熟阶段的探测器(并且可以 按需提供名义成本)，以及涉及更多创新和探索性化学的项目 (这需要更多的原创研究和开发)。核心的供应预算一直是 增加，以更充分地支付这些需求的费用。我们希望修改后的报告充分描述了 我们的整体能力，以及如何为个别项目提供便利。 化学核心专注于开发新的光学试剂。许多光学试剂 已经通过这个核心例行公事地获得了，并且新的代理的合成看起来很好地在 目前工作的范围。虽然MR试剂在研究项目4中描述，但它们的合成是。不 在核心中得到了充分的描述 我们在化学核心的背景下排除了对MR探针能力的描述 在上一次提交的材料中存在疏忽。此外，当时我们设想获得新型的蛋白水解型磁共振 工业来源的项目4的代理。现在我们在[6]节中包括DOTA多肽的合成 对MMPs作用敏感的探头和MR试剂的发展。值得注意的是，我们的化学反应 团队在MR分子显像剂的设计、合成和修饰方面拥有丰富的经验。Dr。 唐·莫廷曾接受过作为磁共振造影剂的金属络合物设计的正式培训，而范博士， 伯恩霍普和曼宁在这一领域发表了许多出版物(见调查人员传记)。此外，Dr。 Pham在设计和开发用于磁共振对比剂的氧化铁剂方面做了大量工作。《核心》 优先次序将由项目的需求决定，总体上更加强调新的光纤 而不是新的核磁共振特工。 核心预算中的一个问题是，曼宁博士也参与了研究项目1，范博士也参与了 研究项目4.目前还不清楚他们的时间将如何分配和计费。 化学核心和研究项目1和4中的努力分配没有反映 曼宁博士和范博士的重复努力。在项目1和项目4中，他们的努力将集中在 关于这些项目所特有的创新发展和探索性化学。他们的 对这些项目的努力分配反映了他们对这些项目的原始智力想法的投资。 然而，除此之外，他们每个人都将对满足其他项目的需求承担更一般的责任。 并通过Core提供已进入更成熟阶段的代理。我们本可以选择 把他们所有的努力都放在核心工作上，但觉得把一些时间分配给具体的项目更能反映出 他们对这些研究项目的密切参与。总体而言，我们认为他们的全部努力是合理的，因为 建议的工作范围。 “一个缺点是，提出b节(设计)中所描述的工作有点不真诚。 作为新的探索性的《建议的新合成化学》的近红外受体淬灭者 已于2002年由核心主任及其顾问出版，当时他是博士后研究员， 哈佛医学院的董医生。‘“ 在我们上一次提交的材料中，我们没有充分传达关于 对NIRQ750的修改是对核心主任 在过去开发的(Pham等人安吉。化学。内部艾德2002、41、3659-62)。我们同意，总体来说，这项工作 在技术上并不新颖，我们现在已经将这种制剂作为一个既定的探测器，将可用。