Chemistry Core

修订提案简介 这是 ICMIC 专业化提案的第一次修订 资源 B，化学核心。申请人感谢评审小组的众多积极评价 以及对先前提交的建设性反馈。显然，审稿人赞赏的价值 核心和优势配套人才和资源致力于发展和 为 ICMIC 的项目提供光学和 MR 试剂。不过，审稿人也有一些 对核心组织的担忧，并认为某些方面没有得到明确描述。在本次修订中， 我们已经解决了上次审查中的所有主要和次要问题，并添加了实质性内容 关于我们提议的核心的功能和结构的大量新的相关信息。核心 人员与上次提交的内容没有变化，在过去的一年里，他们共同努力， 委托新的化学实验室，这将是拟议核心的核心。下面，我们讨论在 详细说明审查中提出的最重要的问题并总结我们的回应。 “不幸的是，这篇核心文章的重点是与四个研究相关的设备和初步工作 项目，而不是对能力的更全面的了解。很少甚至没有讨论费用 结构和商业模式。” 修订后的核心描述已更改，以提供更多关于我们功能的概述，并且 其中一些最能通过仔细研究与具体项目相关的近期成就来最好地说明。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 生产。一般来说，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 指导委员会。各个项目的需求有所不同。我们试图区分 提供已经开发到一定成熟阶段的探针（并且可以 以名义成本“按需”提供），以及涉及更多创新和探索性化学的那些 （并且需要更多的原创研究和开发）。核心的供应预算为 增加以更充分地满足这些需求的成本。我们希望修订后的文章能够充分描述 我们的整体能力，此外还展示了如何促进各个项目。 “化学核心专注于新型光学剂的开发。许多光学剂 已经可以通过该核心常规获得，并且新药物的合成似乎在 当前工作的范围。虽然研究项目 4 中描述了 MR 剂，但它们的合成是。不 核心中充分描述” 我们在化学核心上下文中排除了 MR 探针功能的描述，这是因为 上次提交的监督。此外，当时我们设想获得新型蛋白水解MR 工业源项目4的代理。我们现在将 DOTA 肽的合成纳入第 [6] 节 探针和对 MMP 作用敏感的 MR 试剂的开发。值得注意的是，我们的化学 团队在MR分子成像剂的设计、合成和修饰方面拥有丰富的经验。博士。 Don Molting 接受过作为 MR 造影剂的金属螯合物设计的正式培训，而 Pham 博士则 Bornhop 和 Manning 在该领域发表了许多出版物（参见研究者简介）。此外，博士。 Pham 广泛致力于用于 MR 对比的氧化铁试剂的设计和开发。核心 优先事项将根据项目的需要确定，总体而言，将更加重视新的光学 和核制剂比新的 MR 制剂。 “核心预算中的一个问题是，曼宁博士也参与研究项目 1，而范博士则参与研究项目 1。 研究项目 4。目前尚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 的工作分配并未反映出 博士的重复努力。曼宁和范.在项目 1 和 4 中，他们的工作重点是 关于这些项目特有的特定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创思想的投资。 然而，除此之外，他们每个人都将承担更广泛的责任来满足其他项目的需求 并通过核心提供已进入更成熟阶段的代理。我们本可以选择 将所有精力投入到核心工作中，但感觉将一些时间分配给特定项目更能正确反映 他们密切参与这些研究项目。总的来说，我们认为他们的总体努力是合理的 拟议的工作范围。 “一个弱点是，呈现 b 节（设计的设计）中描述的工作有些不诚实。 近红外受体猝灭剂）的“拟议的新型合成化学”作为新的和探索性的，因为它有 2002 年，当他还是一名博士后研究员时，核心主任和他的顾问已经出版了 哈佛医学院的童博士。” 在我们上次提交的文件中，我们没有充分传达关于以下方面的综合工作： NIRQ750 的修改是对核心主任制定的既定方法的技术修改 过去开发的（Pham 等人 Angew. Chem. Int. Ed. 2002, 41, 3659-62）。我们一致认为这项工作总体上 在技术上并不新颖，我们现在已将此代理作为可用的既定探针包含在内。

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.