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.

修订后的提案简介这是对拟议的ICMIC专业的首次修订 资源B，化学核心。申请人感谢评论小组的许多积极评论 以及有关先前提交的建设性反馈。显然，审阅者赞赏的价值 支持人员和资源的核心和优势，致力于发展和资源 为ICMIC计划提供光学和MR代理。但是，审稿人也有一些 对核心组织的关注，并认为某些方面没有得到清楚的描述。在此修订中， 我们已经解决了上一篇评论的所有主要和次要问题，并增加了大量 有关我们提出的核心的能力和结构的新的相关信息数量。核心 人员与以前的提交保持不变，在过去的一年中，他们共同努力 委托新的化学实验室将成为拟议核心的核心。下面，我们在 详细说明审查中提出的最重要的问题并总结了我们的回应。 “不幸的是，本核心写作重点关注与四项研究相关的设备和初步工作 项目，而不是更全面地了解能力。几乎没有关于费用的讨论 结构和业务模型。” 修订后的核心描述已更改，以提供更多的能力概述，并提供 其中一些可以通过严格研究与特定项目相关的最新成就来最好地说明。我们 现在还包括一个更完整的财务计划，我们已经澄清了与调查相关的费用 生产。通常，核心人员将在执行官的指导下设定核心人员 指导委员会。各个项目的需求有所不同。我们试图区分 提供已经开发到某个成熟阶段的探针的提供（可以是 提供名义成本的“按需”），以及涉及更多创新和探索性化学的人 （以及需要更多原始的研发）。核心的供应预算已经 增加到更充分地满足这些需求的成本。我们希望经过修订的文章能充分描述 我们的整体能力，此外还显示了如何促进各个项目。 “化学核心集中于新的光学剂的开发。许多光学剂 已经通过此核心常规可用，而新的代理的合成似乎很好 当前工作的范围。尽管MR代理在研究项目4中描述了它们的合成。不是 在核心中充分描述” 我们在化学核心背景下对MR探测能力的描述的排除是 先前提交中的监督。此外，当时我们设想获得新的蛋白水解MR 项目4的代理商来自工业来源。现在，我们在第[6]中包括DOTA肽的合成 探针和MR剂的发展对MMP的影响敏感。值得注意的是我们的化学反应 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已在金属螯合物的设计中正式训练为MR对比剂，而Drs Pham博士， Bornhop和Manning在该领域有许多出版物（请参阅调查员Bio-Sketches）。另外，博士 PHAM在MR对比度上的设计和开发方面已广泛地工作。核心 优先级将由项目的需求确定，总体而言，更加重视新的光学 和核代理人比新先生代理人。 “核心预算中的一个问题是曼宁博士也在研究项目1上，Pham博士正在开启 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的努力分配并不反映 Drs的努力重复。曼宁和pham。在项目1和4中，他们的努力将集中在 在特定于这些项目的特定创新发展和探索性化学上。他们的 向这些项目的努力分配反映了他们对这些计划的原始智力思想的投资。 但是，他们每个人都将对满足其他项目的需求负有更大的一般责任 并通过核心提供已经发展到更成熟阶段的代理商。我们本可以选择 将所有的努力放在核心中，但会更恰当地将他们的一些时间分配给特定项目 他们密切参与了这些研究计划。总的来说，我们认为他们的全部努力是合理的 提议的工作范围。 “一个弱点是介绍B节中描述的作品有些不明智（设计 “提出的新型合成化学”的NIR受体淬灭者，因为它具有 核心董事及其顾问在2002年发表了他的顾问。 哈佛医学院的顿博士。'' 在上次提交中，我们没有充分传达有关有关的合成工作 NIRQ750的修改是核心主管的既定方法的技术修正案 过去开发（Pham等人Angew。Chem。Int。2002，41，3659-62）。我们同意这项工作总体 在技​​术上不是新颖的，我们现在将该代理作为可以使用的既定探针。