Glycated CD59 as a novel biomarker of gestational diabetes mellitus

糖化 CD59 作为妊娠期糖尿病的新型生物标志物

基本信息

批准号：
8374166
负责人：
JOSE A HALPERIN
金额：
$ 25.6万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374166
关键词：
Active Sites Address Admission activity Affect Age Alloantigen American American College of Obstetricians and Gynecologists Biological Assay Biological Markers Birth Weight Birth trauma Blood specimen Body Weight CD46 Antigen Caring Clinical Clinical Data Clinical Research Collection Complement Complement Membrane Attack Complex Complications of Diabetes Mellitus Cross-Sectional Studies Data Development Diabetes Mellitus Diagnosis Diagnostic Disease Early Diagnosis Enzyme-Linked Immunosorbent Assay Equipment Failure Fasting Fetal Macrosomia Fetus First Pregnancy Trimester Freezing Functional disorder Gestational Age Gestational Diabetes Glucose Glucose Intolerance Glycosylated hemoglobin A Goals Gold Graft Rejection Hospitals Human Hyperglycemia Hyperinsulinism Hypoglycemia Immune response Immune system Individual Intake Laboratories Laboratory Research Link Liquid substance Measures Mediating Membrane Proteins Methods Monoclonal Antibodies Mutation NIH Program Announcements Nausea and Vomiting Neonatal Intensive Care Units OGTT Organ Organ Transplantation Pathogenesis Patients Perinatal Play Population Heterogeneity Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Prenatal care Prevention Professional Organizations Publications Reagent Reproducibility Research Project Grants Risk Role Sampling Screening procedure Sensitivity and Specificity Serum Site Source Testing Third Pregnancy Trimester Time Tissues Translations United States Urine Validation Woman Work adverse outcome base clinical practice clinically relevant cohort complement system design diabetic fetal genetic regulatory protein glucose tolerance glycation innovation meetings non-diabetic novel pregnant prevent programs prospective public health priorities standard of care success tool trophoblast

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to assess glycated CD59 in human serum as a pathogenically relevant early bio-marker for screening of gestational diabetes mellitus (GDM). This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) and GDM is a major source of adverse pregnancy outcomes including macrosomia and pre-eclampsia. The proposed work opens the possibility of using glyCD59 as a biomarker for GDM, an innovative departure from the use of OGTT, a cumbersome, costly and time-consuming test with poor reproducibility and many times unwanted effects including nausea and vomiting. A simpler, easy to use, patient friendly marker that is also involved in the pathogenesis of diabetes and its complications may help fulfill an important clinical need in the widespread screening for GDM and prevention of associated adverse outcomes. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents that allow quantification of glycated hCD59 in human fluids and tissues. Specifically, we have demonstrated that 1) glycated CD59 is present in target organs of diabetic complications, and 2) glyCD59 can be readily measured in normal urine and serum. Furthermore, our preliminary data show that glyCD59 is a) significantly increased (3-4 fold) in the serum of diabetic and pre-diabetics individuals, and b) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aim are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for glycated CD59 and assay calibrators, access to large and diverse population of pregnant women undergoing pre-natal care at BWH, and diagnostic tools, equipment and expertise to necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in screening and early diagnosis of GDM. PUBLIC HEALTH RELEVANCE: This highly translational proposal a) aims at establishing serum glycated CD59 as a novel biomarker of Gestational Diabetes Mellitus (GDM), b) is based on robust preliminary data and availability of all assays/reagents needed, and c) addresses major Public Health priorities. The importance of this goal is highlighted by the fact that 1) GDM occurs in 1 to 14% of all pregnancies, and is rising in the United States, 2) GDM is a major cause of adverse pregnancy outcomes including macrosomia, pre-eclampsia C-sections, hyperinsulinemia, 3) adverse outcomes can be prevented with adequate treatment, 4) screening for GDM with OGTT at 24-28th weeks is now the standard of care for most pregnant women seeking prenatal care in the United States, and 5) oral glucose tolerance test (OGTT), the current gold standard for GDM screening, is cumbersome, uncomfortable, at times causes nausea and vomiting and is not fully reproducible. Success will allow the use of a simpler, cheaper, more patient-friendly and accurate screening test for GDM.

描述（由申请人提供）：该提案的目的是评估人血清中的CD59，作为筛查妊娠糖尿病（GDM）的病原体相关的早期生物标志物。该提案高度转化，并解决了主要的公共卫生优先事项，因为1）糖尿病会影响2500万美国人，2）和GDM是不良妊娠结局的主要来源，包括巨糖症和先兆子痫。拟议的工作打开了使用GLYCD59作为GDM的生物标志物的可能性，这是与使用OGTT的创新性，这是一项繁琐的，昂贵且耗时的测试，可再现性差，许多次不需要的效果，包括恶心和呕吐。一个更简单，易于使用的，患者友好的标记也参与了糖尿病的发病机理及其并发症，可能有助于满足GDM广泛筛查和预防相关不良结果的重要临床需求。申请人有1）发现人CD59被糖基化灭活，2）提供了补体系统与糖尿病并发症的发病机理之间的联系的证据，以及3）开发了关键试剂，允许在人体液体和组织中量化糖化的HCD59。具体而言，我们已经证明了1）糖尿病并发症的靶器官中存在糖化的CD59，而2）可以在正常的尿液和血清中轻松测量GlyCD59。此外，我们的初步数据表明，糖尿病和糖尿病前个体的血清中GlyCD59是a）明显增加（3-4倍），而b）似乎比HBA1C更快地响应了对个体内部所有必要的工具和专业知识中的GLACEPAT负载的变化，以使我们的目的在我们的目标9中都可以使用。测定校准器，在BWH处获得大量和多样化的孕妇，以及诊断工具，设备和专业知识，以进行应用中提出的所有研究。成功实现我们的目标将代表GDM筛查和早期诊断的重大进步。公共卫生相关性：这项高度转化的建议a）旨在建立血清糖化的CD59作为妊娠糖尿病的新生物标志物（GDM），b）基于强大的初步数据和所需的所有试验/试剂的可用性，并且c）解决了重大公共卫生优先级。 1）GDM发生在所有怀孕的1-14％中，并且在美国正在上升，2）GDM是造成不良怀孕结果的主要原因，包括巨糖症，包括宏观稀有症状的不良症状，在美国的不良症状，在美国的不良治疗中，超胰岛素的不良疗法，o o o o o o o o o o o o o o o o o o o y to to o o o o o o o o o o o o o怀的。现在，第24-28周是大多数在美国寻求产前护理的孕妇的护理标准，以及5）口服葡萄糖耐量测试（OGTT），当前的GDM筛查的金标准是笨拙，不舒服，有时会导致恶心和呕吐，并且不完全可再现。成功将允许对GDM进行更简单，更便宜，更适合患者的筛查测试。