Elucidating the properties of low-molecular-weight chromuim-binding substance

阐明低分子量铬结合物质的特性

• 批准号: 7078835
• 负责人: JOHN Bertram VINCENT
• 金额: $ 17.8万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078835
• 关键词: chromium; clinical research; insulin; molecular weight

DESCRIPTION (provided by applicant): Over 16 million people in the US have diabetes mellitus. Nearly 95% of these cases are of type 2 diabetes. Type 2 diabetes is responsible for the rapid increase in diabetes cases over the last few decades and is associated with insulin resistance. The body produces insulin normally (at least at first); however, the insulin signal is not properly transmitted into cells. Any mechanism by which insulin sensitivity might be enhanced has potential value in the treatment of symptoms of type 2 diabetes and other conditions related to insulin resistance (hypertension, cardiovascular disease, etc.). Chromium has been proposed to play a role in insulin signaling, and pharmacological doses of chromium have beneficial effects in diabetic patients and model animals. Understanding at a molecular level the role of chromium in insulin-signaling enhancement could lead to development of chromium-bsaed drugs for the treatment of diabetes. The importance of chromium was recently recognized by NCCAM through the funding program "Chromium as adjuvant therapy for type 2 diabetes and impaired glucose tolerance" (PA-01-114). Elucidating the role of chromium in enhancing insulin sensitivity has been hindered by a couple of experimental problems. First, the pathway by which chromium is distributed in the body has not been completely elucidated. Chromium in tissues such as liver and kidney is bound by the oligopeptide low-molecular weight chromium-binding substance (LMWCr) or chromodulin, which has been proposed to have a role in enhancing insulin signaling by interacting with insulin receptor. However, while LMWCR has been well characterized spectroscopically and magnetically, the oligopeptide has proven difficult to sequence and detect in biological matrices. The specific aims of this work are 1) to develop and utilize procedures for analyzing chromium-containing macromolecules by mass spectrometry, most notably highly acidic peptides and their Cr complexes including their fragmentation pathways, 2) to apply this knowledge to sequencing LMWCr (chromodulin) and related chromium-containing peptides, and 3) to determine the nature of the low-molar mass chromium-binding component of urine, postulated to be LMWCr. The approach will employ two advancing methodologies in mass spectrometry: electrospray ionization Fourier transform ion cyclotron resonance (ESI/FT-ICR) and matrix-assisted laser desorption ionization time-of-flight (MALDI/TOF).

描述（由申请人提供）：美国有超过 1600 万人患有糖尿病。其中近 95% 的病例属于 2 型糖尿病。 2 型糖尿病是过去几十年糖尿病病例迅速增加的原因，并且与胰岛素抵抗有关。身体正常产生胰岛素（至少一开始是这样）；然而，胰岛素信号没有正确传输到细胞中。任何可能增强胰岛素敏感性的机制在治疗 2 型糖尿病症状和与胰岛素抵抗相关的其他疾病（高血压、心血管疾病等）方面都具有潜在价值。铬被认为在胰岛素信号传导中发挥作用，药理学剂量的铬对糖尿病患者和模型动物具有有益作用。在分子水平上了解铬在胰岛素信号增强中的作用可能会导致开发用于治疗糖尿病的铬药物。 NCCAM 最近通过资助计划“铬作为 2 型糖尿病和糖耐量受损的辅助疗法”(PA-01-114) 认识到了铬的重要性。一些实验问题阻碍了阐明铬在增强胰岛素敏感性方面的作用。首先，铬在体内的分布途径尚未完全阐明。肝脏和肾脏等组织中的铬与寡肽低分子量铬结合物质 (LMWCr) 或染色调节蛋白结合，有人认为其通过与胰岛素受体相互作用，具有增强胰岛素信号传导的作用。然而，虽然 LMWCR 已通过光谱和磁性得到了很好的表征，但事实证明该寡肽难以在生物基质中进行测序和检测。这项工作的具体目标是 1) 开发和利用通过质谱分析含铬大分子的程序，尤其是高酸性肽及其 Cr 复合物，包括其断裂途径，2) 将这些知识应用于 LMWCr（染色调节蛋白）和相关含铬肽的测序，以及 3) 确定低摩尔质量铬结合成分的性质 尿液，假设为 LMWCr。该方法将采用两种先进的质谱分析方法：电喷雾电离傅里叶变换离子回旋共振（ESI/FT-ICR）和基质辅助激光解吸电离飞行时间（MALDI/TOF）。