2014 Sheep Request - Acquisition of a GC/MS/MS Instrument for State-of-the-Art Neurosteroid Quantification

 描述(由申请人提供)： 我们的达勒姆弗吉尼亚州实验室是国际上为数不多的能够使用高灵敏度和特定的“金标准”质谱学技术对神经类固醇(富含在大脑中的内源性分子)进行定量的实验室之一。这一最先进的方法在2004-2005年间在我们位于达勒姆退伍军人管理局医学中心的实验室进行了优化和验证，并于2006年发表了第一篇同行评议的手稿(请参阅附录以供列出，其中包括生物精神病学[影响因子10.3]的2篇“优先沟通”和神经精神药理学[影响因子7.8]的4篇手稿)。这些出版物涉及与多名退伍军人管理局调查人员的合作，包括当地和全国各地。在啮齿动物模型和人类死后脑组织中进行的早期神经类固醇生物标记物研究已迅速转化为概念验证临床试验，测试神经类固醇在患有精神分裂症、创伤性脑损伤、创伤后应激障碍、疼痛状况和其他中枢神经系统疾病的退伍军人队列中的药理干预作用。我们目前为这些研究保留了4个FDA研究新药编号，这是由于基础科学‘工作台’的努力迅速转化为临床研究的结果。此外，与这些专注于使用神经类固醇和衍生物治疗中枢神经系统疾病的技术相关的未决专利由退伍军人管理局和杜克大学共同拥有(208项豁免到位，见附录)。我们的第一台质谱仪是在2001年购买的--安捷伦5973气相色谱/质谱仪(GC/MS)，我们目前正在使用它进行神经类固醇分析项目(通过它，我们已经实现了神经类固醇定量的毫微摩尔灵敏度)。遗憾的是，自2014年9月起，安捷伦将不再以服务合同支持该GC/MS仪器，因为该GC/MS仪器是在12年前购买的，从行业支持的角度来看，它被认为是“过时的”，因此安捷伦将不再保证维修、服务或更换部件。因此，目前和未来的VA神经类固醇项目都面临风险。具体地说，多项退伍军人管理局研究和多名退伍军人管理局调查人员依赖于这种神经类固醇量化能力，以完成退伍军人管理局功绩审查赠款和职业发展奖的资助目标。此外，退伍军人研究人员继续获得这项有价值的技术将对利用新的科学线索开发新的疗法来治疗影响大量退伍军人的疾病至关重要。在退伍军人管理局继续拥有质谱学能力也是至关重要的，因为一些高影响力的期刊现在需要质谱学方法-并且将不再发表免疫分析方法学(自2015年1月1日起，J Clin Endocrinol Metab；见附录)。因此，更换GC/MS仪器是退伍军人管理局迫切而关键的科学需求。因此，我们请求采购一台GC/MS/MS仪器，以便：1.)更换目前的GC/MS仪器，我们不能再获得维修合同，而且由于缺乏维修支持和更换部件2，这些仪器很快将无法使用。)通过购买GC/MS/MS仪器来改进目前的GC/MS方法，以便：a.进一步提高方法灵敏度，因为GC/MS/MS仪器比我们目前的GC/MS仪器更灵敏，因此可能需要更少的劳动密集型样品制备；因此，它将增加我们的总体样品吞吐量和能力，使其能够与更多的退伍军人管理局研究人员合作，并满足对这项技术日益增长的需求(某些高影响力的期刊现在也要求发表这项技术)。

 DESCRIPTION (provided by applicant): Our Durham VA laboratory is fortunate to be one of few laboratories internationally with the capacity to quantify neurosteroids (endogenous molecules enriched in brain) using highly sensitive and specific `gold standard' mass spectrometry-based technologies. This state-of-the-art methodology was optimized and validated in our lab at the Durham VA Medical Center in 2004-2005, and the first peer-reviewed manuscripts utilizing this technology were published in 2006 (please see Appendix for listing, which includes 2 "Priority Communications" in Biological Psychiatry [impact factor 10.3] and 4 manuscripts in Neuropsychopharmacology [impact factor 7.8]). These publications involved collaborations with multiple VA investigators, both locally and across the country. Early neurosteroid biomarker investigations in rodent models and human postmortem brain tissue have been rapidly translated to proof-of-concept clinical trials testing neurosteroids as pharmacological interventions in Veteran cohorts with schizophrenia, traumatic brain injury, post-traumatic stress disorder, pain conditions, and other CNS disorders. We currently hold 4 FDA Investigational New Drug numbers for these studies, resulting from rapid translation of basic science `bench' efforts to clinical investigations. Also, pending patents related to these technologies focusing on use of neurosteroids and derivatives for the treatment of CNS conditions are co-owned by VA and Duke (208 waiver in place, see Appendix). Our first mass spectrometry instrumentation was purchased in 2001 - an Agilent 5973 gas chromatography/mass spectrometry (GC/MS) instrument that we are currently utilizing for our neurosteroid analytic projects (and with which we have achieved femtomolar sensitivity for neurosteroid quantification). Unfortunately, as of September 2014, Agilent will no longer support this GC/MS instrument with a service contract - because the GC/MS instrument was purchased over 12 years ago, it is considered "obsolete" from an industry support perspective, and thus Agilent will no longer guarantee repairs, service, or replacement of parts. As a result, current and future VA neurosteroid projects are at risk. Specifically, multiple VA studies and multiple VA investigators depend on this neurosteroid quantification capacity in order to complete the aims of funded VA Merit Review grants and Career Development Awards. Further, continued availability of this valuable technology to VA investigators will be pivotal to leveraging new scientific leads for development of novel therapeutics to treat conditions impacting large numbers of Veterans. It is also essential to have continued mass spectrometry capacity at VA because some high-impact journals are now requiring mass spectrometry approaches - and will no longer publish immunoassay methodologies (as of January 1, 2015 for J Clin Endocrinol Metab; see Appendix). The replacement of the GC/MS instrumentation is thus an urgent and critical scientific need for VA. We therefore request acquisition of a GC/MS/MS instrument in order to: 1.) Replace the current GC/MS instrument, for which we can no longer obtain a service contract and which will soon be rendered unusable secondary to absence of repair support and replacement parts 2.) Improve upon the current GC/MS methodology via acquisition of a GC/MS/MS instrument in order to: a. Further increase methodological sensitivity, as the GC/MS/MS instrument is even more sensitive than our current GC/MS instrument, thus likely requiring less labor-intensive sample preparation; thereby it would b. Increase our overall sample throughput and capacity, making it possible to collaborate with more VA investigators and to meet the ever-increasing demand for this technology (which certain high-impact journals are now also requiring for publication)