公开(公告)号：US07910323B2

公开(公告)日：2011-03-22

申请号：US12403331

申请日：2009-03-12

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： C12Q1/54

CPC分类号： G01N33/58 ,  A61K49/0004

摘要： Provided herein are methods for determining the metabolism of one or more sugars and/or fatty acids, and applications thereof. Such applications include determining the rate of glycogen synthesis and glycolysis, which are believed to be early markers for predicting elevated risk of diabetes and cardiovascular disease. Other applications include methods for screening drugs that effect sugar and/or fatty acid metabolism. The methods are useful for at least partially characterizing drugs for desirable or undesirable (toxic) characteristics. Drugs that are at least partially characterized using the methods of the invention can then be further developed in pre-clinical testing and clinical trials. Such drugs may be found to be useful in treating obesity, diabetes, cardiovascular disease, and other disorders of metabolism.

摘要翻译： 本文提供了确定一种或多种糖和/或脂肪酸的代谢的方法及其应用。 这些应用包括确定糖原合成和糖酵解的速率，这被认为是预测糖尿病和心血管疾病风险升高的早期标志物。 其他应用包括用于筛选影响糖和/或脂肪酸代谢的药物的方法。 所述方法可用于至少部分表征药物以获得期望的或不期望的（有毒的）特征。 可以在临床前临床试验和临床试验中进一步开发使用本发明方法至少部分表征的药物。 可以发现这些药物可用于治疗肥胖，糖尿病，心血管疾病和其他代谢紊乱。

公开(公告)号：US20090041661A1

公开(公告)日：2009-02-12

申请号：US12173784

申请日：2008-07-15

申请人： Marc K. HELLERSTEIN

发明人： Marc K. HELLERSTEIN

IPC分类号： A61K51/00

CPC分类号： A61K51/0493 ,  G01N33/5091 ,  G01N33/58 ,  G01N33/60 ,  G01N33/6842 ,  G01N33/6848 ,  G01N2800/52 ,  Y10T436/24 ,  Y10T436/25

摘要： Methods of determining rate of biosynthesis or breakdown of biological molecules from metabolic derivatives and catabolic products are disclosed herein. In particular, methods of measuring the rates of biosynthesis and breakdown of biological molecules inaccessible or not easily accessible to direct sampling by sampling metabolic derivatives and catabolic products in accessible biological samples are disclosed herein.

摘要翻译： 本文公开了鉴定代谢衍生物和分解代谢产物的生物合成或分解生物分子的速率的方法。 特别地，本文公开了测量生物分子的速率的方法，其不可访问或不易于通过在可及的生物样品中取样代谢衍生物和分解代谢产物直接取样。

公开(公告)号：US07449171B2

公开(公告)日：2008-11-11

申请号：US10366125

申请日：2003-02-12

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： A61K49/00 ,  A61K33/00 ,  C12Q1/00

CPC分类号： A61K51/0493 ,  G01N33/5091 ,  G01N33/58 ,  G01N33/60 ,  G01N33/6842 ,  G01N33/6848 ,  G01N2800/52 ,  Y10T436/24 ,  Y10T436/25

摘要： Methods of determining rate of biosynthesis or breakdown of biological molecules from metabolic derivatives and catabolic products are disclosed herein. In particular, methods of measuring the rates of biosynthesis and breakdown of biological molecules inaccessible or not easily accessible to direct sampling by sampling metabolic derivatives and catabolic products in accessible biological samples are disclosed herein.

摘要翻译： 本文公开了鉴定代谢衍生物和分解代谢产物的生物合成或分解生物分子的速率的方法。 特别地，本文公开了测量生物分子的速率的方法，其不可访问或不易于通过在可及的生物样品中取样代谢衍生物和分解代谢产物直接取样。

公开(公告)号：US20080187937A1

公开(公告)日：2008-08-07

申请号：US11573374

申请日：2005-08-08

申请人： Marc K. Hellerstein ,  Patrizia Fanara

发明人： Marc K. Hellerstein ,  Patrizia Fanara

IPC分类号： G01N33/567 ,  G01N33/53

CPC分类号： G01N33/58 ,  G01N33/6896 ,  G01N2458/15 ,  G01N2500/00

摘要： The Applicants have established a simple, rapid assay of measuring the dynamics of self-assembling systems of biological molecules, based on stable isotope labeling technology that can be used in intact animals including humans. Examples of self-assembling systems of biological molecules include microtubule polymers, actin filaments, amyloid-beta plaques or fibrils, prion plaques or fibrils, fibrin aggregates, tau filaments (e.g., neurofibrillary tangles), α-synuclein filaments, and mutant hemoglo-bin aggregates. The method reveals constitutive differences in the dynamics of assembly and disassembly between tissues and is sensitive to the action of compounds that stabilize these dynamics.

摘要翻译： 申请人已经建立了一种基于稳定同位素标记技术测量生物分子自组装系统动力学的简单，快速的方法，该技术可用于包括人类在内的完整动物。 生物分子的自组装系统的实例包括微管聚合物，肌动蛋白丝，淀粉样蛋白-β斑或原纤维，朊病毒斑或原纤维，纤维蛋白聚集体，tau细丝（例如神经原纤维缠结），α-突触核蛋白丝和突变体血红蛋白 聚合。 该方法揭示了组织之间的组装和拆卸的动力学的组成性差异，并且对稳定这些动力学的化合物的作用敏感。

公开(公告)号：US07357913B2

公开(公告)日：2008-04-15

申请号：US11433879

申请日：2006-05-11

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： A61N51/00

CPC分类号： G01N33/502 ,  G01N33/5088 ,  G01N2800/52

摘要： The invention relates to techniques for measuring and comparing relative molecular flux rates of different biological molecules by administering isotope-labeled water to one or more tissues or individuals and comparing the molecular flux rates of two or more biological molecules, including biological molecules in different chemical classes. The methods find use in several applications including diagnosing, prognosing, or monitoring a disease, disorder, or condition, the in vivo high-throughput screening of chemical entities and biological factors for therapeutic effects in various disease models, and the in vivo high-throughput screening of chemical entities and biological factors for toxic effects.

摘要翻译： 本发明涉及通过向一个或多个组织或个体施用同位素标记的水并比较两种或多种生物分子（包括不同化学类别中的生物分子）的分子通量速率来测量和比较不同生物分子的相对分子通量速率的技术 。 该方法可用于多种应用，包括诊断，预后或监测疾病，病症或状况，化学实体的体内高通量筛选和各种疾病模型中治疗效果的生物因子，以及体内高通量 筛选化学实体和生物因素的毒性作用。

公开(公告)号：US07255850B2

公开(公告)日：2007-08-14

申请号：US10519121

申请日：2003-09-15

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： A61K51/00 ,  A61M36/14

CPC分类号： A61K49/0004 ,  A61K51/04 ,  A61K51/0493 ,  A61K51/1224

摘要： The present invention relates to biochemical methods for determining reverse cholesterol transport. Specifically, the rates of the two arms of reverse cholesterol transport (HDL or first arm and post-HDL or second arm) are obtained by measuring the flow of unlabeled cholesterol from tissues into plasma HDL and from plasma HDL to bile acids.

摘要翻译： 本发明涉及用于测定反向胆固醇转运的生物化学方法。 具体地说，通过测量未标记的胆固醇从组织到血浆HDL的流量以及从血浆HDL到胆汁酸，可获得反向胆固醇转运的两个臂（HDL或第一臂和后HDL或第二臂）的速率。

公开(公告)号：US07022834B2

公开(公告)日：2006-04-04

申请号：US10944154

申请日：2004-09-16

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： C07H21/00

CPC分类号： A61K31/665 ,  C12Q1/48 ,  C12Q1/68 ,  C12Q1/6809 ,  C12Q1/70 ,  G01N33/5005 ,  G01N33/5088 ,  G01N33/60

摘要： The present invention relates to a labeled deoxyribonucleic acid (DNA) molecule. In one aspect, the labeled DNA molecule is produced by contacting a cell or subject with a detectable amount of a stable isotope label which is incorporated into DNA via the de novo nucleotide synthesis pathway to produce the labeled DNA molecule.

摘要翻译： 本发明涉及标记的脱氧核糖核酸（DNA）分子。 在一个方面，标记的DNA分子是通过使细胞或受试者与可检测量的稳定同位素标记物接触产生的，所述稳定同位素标记物通过从头核苷酸合成途径并入DNA中以产生标记的DNA分子。

公开(公告)号：US5338686A

公开(公告)日：1994-08-16

申请号：US876752

申请日：1992-04-29

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： A61K51/04 ,  G01N31/00 ,  G01N24/00 ,  G01N33/543

CPC分类号： A61K51/04 ,  Y10T436/24 ,  Y10T436/25 ,  Y10T436/25375

摘要： A method for determining the mass isotope enrichment of a subunit from which a biopolymer is formed, and the rates of synthesis and decay of the biopolymer. The mass isotope enrichment of the subunit is determined by comparing the mass isotopomer distribution of the biopolymer after administration of a mass isotopically labeled subunit, with the expected frequencies of the different mass isotopomers produced from a given subunit mass isotope enrichment. To determine the synthesis rate of the biopolymer, the expected frequency of a selected biopolymer mass isotopomer, calculated from the subunit isotope enrichment, is compared with the actual frequency of that biopolymer mass isotopomer. To determine biopolymer decay, the decay rate of high mass isotopomers of the biopolymer is determined.

摘要翻译： 用于确定形成生物聚合物的亚基的质量同位素富集的方法以及生物聚合物的合成和衰变速率。 通过比较施用质量同位素标记的亚基后生物聚合物的质量同位素分布与从给定亚单位质量同位素富集产生的不同质量同位素的预期频率来确定亚单位的质量同位素富集。 为了确定生物聚合物的合成速率，将从亚基同位素富集计算的所选生物聚合物质量同位素的预期频率与该生物聚合物质量同位素的实际频率进行比较。 为了确定生物聚合物衰变，确定生物聚合物的高质量同位素的衰变速率。

公开(公告)号：US08741589B2

公开(公告)日：2014-06-03

申请号：US11451735

申请日：2006-06-12

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： C12Q1/54

CPC分类号： A61K49/0008 ,  A61K49/0004 ,  G01N33/60 ,  G01N33/6893 ,  G01N2800/042

摘要： Provided are methods for determining concurrently with a simple, minimally invasive test, the adequacy of pancreatic beta-cell compensation and/or the presence of tissue insulin resistance in a subject human or an experimental animal. The methods allow for the determination of a subject's or experimental animal's susceptibility to developing type 2 diabetes mellitus (DM2) or to progression to more advanced forms of DM2. Among other uses, the methods allow for diagnostic classification of subjects for decisions regarding therapeutic interventions, clinical differentiation between type 1 DM and DM2, clinical monitoring of treatments intended to reduce risk of developing DM2 in non-diabetic subjects, clinical monitoring of agents intended to improve existing DM2 and to prevent progression of DM2, clinical development and testing of new compounds, candidate agents, or candidate therapies for preventing progression to DM2 or disease progression in existing DM2, and preclinical screening of candidate agents or candidate therapies in experimental animals to identify and characterize agents having insulin-sensitizing properties, pancreatic stimulatory or regenerative properties or other desirable actions.

摘要翻译： 提供了用于通过简单的微创测试同时测定胰腺β细胞补偿的充分性和/或受试者或实验动物中组织胰岛素抵抗的存在的方法。 该方法允许确定受试者或实验动物对发展为2型糖尿病（DM2）的敏感性或进展至更高级的DM2形式。 除了其他用途之外，这些方法允许受试者的诊断分类用于治疗干预，1型DM和DM2之间的临床分化，旨在降低在非糖尿病受试者中发展DM2的风险的治疗的临床监测，旨在 改善现有的DM2，并防止DM2的进展，新化合物，候选药物或候选药物的临床开发和检测，以防止DM2进展或现有DM2中的疾病进展，以及临床前筛选实验动物中的候选药物或候选治疗，以鉴定 并表征具有胰岛素敏感性，胰刺激或再生性质或其它期望作用的药剂。

公开(公告)号：US08663602B2

公开(公告)日：2014-03-04

申请号：US13031084

申请日：2011-02-18

申请人： Marc K. Hellerstein

发明人： Marc K. Hellerstein

IPC分类号： A61K49/00

CPC分类号： G01N33/5067 ,  A61K49/0008 ,  G01N33/5088 ,  G01N33/60 ,  G01N33/6848 ,  Y02A90/22

摘要： The invention enables high-throughput screening of compounds in living systems to detect unanticipated or unintended biological actions. The invention also allows for screening, detection, and confirmation of new indications for approved drugs. Screening and detection of toxic effects of compounds also can be achieved by using the methods of the invention. The methods comprise administering isotope-labeled substrates to a living system so that the label is incorporated into molecules in a manner that reveals flux rates through metabolic pathways thought to be involved in a disease. Comparisons between living systems exposed to compounds and living systems not so exposed reveals the effects of the compounds on the flux rates through the metabolic pathways. Combinations or mixtures of compounds can be systematically screened to detect unanticipated or unintended biological actions, including synergistic actions, in the same manner.

摘要翻译： 本发明使得生物系统中化合物的高通量筛选能够发现未预期的或非预期的生物作用。 本发明还允许筛选，检测和确认经批准的药物的新适应症。 化合物的毒性作用的筛选和检测也可以通过使用本发明的方法来实现。 所述方法包括向活体系统施用同位素标记的底物，使得将标记以通过被认为参与疾病的代谢途径揭示通量速率的方式并入分子中。 暴露于化合物的活体系与未暴露的生物体系之间的比较揭示了化合物对通过代谢途径的通量速率的影响。 可以以相同的方式系统地筛选化合物的组合或混合物以检测意外的或非预期的生物作用，包括协同作用。