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）：美国超过1600万人患有糖尿病。这些病例中近95％是2型糖尿病。 2型糖尿病是在过去的几十年中导致糖尿病病例迅速增加的原因，并且与胰岛素抵抗有关。身体通常会产生胰岛素（至少起初）；但是，胰岛素信号未正确传播到细胞中。任何可能增强胰岛素敏感性的机制在治疗2型糖尿病症状以及与胰岛素抵抗（高血压，心血管疾病等）的其他疾病方面具有潜在价值。已经提出铬在胰岛素信号传导中发挥作用，并且铬的药理学剂量对糖尿病患者和模型动物具有有益的作用。在分子水平上了解铬在胰岛素信号增强中的作用可能导致铬肉的药物的发展来治疗糖尿病。 NCCAM最近通过“铬作为2型糖尿病的辅助治疗和葡萄糖耐受性受损”（PA-01-114）认识到铬的重要性。阐明铬在增强胰岛素敏感性方面的作用受到了一些实验问题的阻碍。首先，铬分布在体内的途径尚未完全阐明。肝脏和肾脏等组织中的铬受寡肽低分子量铬结合物质（LMWCR）或染色蛋白的结合，该铬蛋白已被提议通过与胰岛素受体相互作用来在增强胰岛素信号传导中起作用。但是，尽管LMWCR在光谱和磁性上的表征都得到了很好的特征，但事实证明，寡肽在生物基质中很难进行测序和检测。这项工作的具体目的是1）开发和利用程序来通过质谱法分析含铬的大分子，最值得注意的是高度高度酸性肽及其CR复合物，包括其碎裂途径，2）将这些知识应用于测序的LMWCR（Chromodulin）和相关铬粒的质量质量和3个以下的peptiment和3），以确定peptides和3），以确定peptives and Chrominds and Chromind oblement of-natire ofering oblement of-natire of chroming oblement of-natire of 3），以构成3个元素的构图，以下方面的3）尿液，假定为LMWCR。该方法将在质谱法中采用两种前进的方法：电喷雾傅立叶变换离子离子共振（ESI/FT-ICR）和基质辅助激光解吸电离飞行时间（MALDI/TOF）。