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Environmental Causes of Type 1 Diabetes

1 型糖尿病的环境原因

基本信息

批准号：
7192422
负责人：
MARIAN J REWERS
金额：
$ 83.36万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7192422
关键词：
Address Affect Age Age-Months Alleles Appearance Autoantibodies Autoimmunity Award Birth Birth Order Blood Screening Cells Centers for Disease Control and Prevention (U.S.)Cereals Child Childhood Cities Clinical Collaborations Colorado Cytomegalovirus DNA Data Data Analyses Data Collection Data Coordinating Center Day Care Development Diabetes Mellitus Diabetes autoantibodies Diet Enrollment Enterovirus Environment Environmental Exposure Environmental Risk Factor Epitopes Ethnic Origin Evaluation Exposure to Face Family history of First Degree Relative Frequencies Funding General Population Genes Genetic Genetic Markers Genetic Polymorphism Genetic Risk Genotype Goals HLA-A Antigens HLA-A gene HLA-A2 Antigen HLA-DRB1*0401 Haplotypes Health Sciences Herpesvirus 1 Household Human Genetics Human Herpesvirus 2 Human Herpesvirus 4 IA-2 protein IgG4 Immunization Immunoglobulin Class Switching Immunoglobulin G Incidence Infant Infection Instruction Insulin Insulin-Dependent Diabetes Mellitus Intake Intercellular adhesion molecule 1 Laboratories Licensing Life Measurement Meat Molecular Names Natural History Newborn Infant Parents Patients Persons Population Principal Investigator Printing Production Protocols documentation Psychologist Race Relative (related person)Relative Risks Research Personnel Research Project Grants Resolution Risk Rotavirus Sampling Screening procedure Siblings Specimen Standards of Weights and Measures Supplementation System T-Lymphocyte Time Umbilical Cord Blood Universities Vaccination Vaccines Viral Viral Antibodies Vitamin D Vitamins Woman case control cohort diabetic early childhood environmental agent experience follow-up fruits and vegetables gene environment interaction human leukocyte antigen gene in utero islet men pet animal proband programs promoter prospective receptor response transmission process viral RNA

项目摘要

This proposal is in response to the RFA-DK02-029 "Consortium For Identification Of Environmental Triggers Of Type 1 Diabetes". Our experience in this field comes from the Diabetes Autoimmunity Study in the Young (DAISY, DK32493, M. Rewers, P.I., 7/93-6/06). DAISY began in July 1993 and allowed us to establish two unique cohorts of very young children who are at up to 20-fold increased risk of type 1 diabetes (T1DM). Prospective follow-up of these cohorts similar studies elsewhere have already provided important information concerning the natural history of b-cell autoimmunity and diabetes in early childhood, including candidate environmental triggers, but also led to the realization that definitive answers will require a large-scale collaborative effort and gave impetus to this RFA. We are proposing to address the following Specific Aims: 1. In collaboration with the other CCs and the DCC, develop standard screening and follow-up protocols to establish cohorts of 5200 general population newborns and 500 newborn relatives of T1DM patients with high-moderate genetic risk of T1DM. The intent is to follow these cohorts for islet autoantibodies and diabetes until the age of 15 years in order to identify environmental triggers of pre-diabetes and promoters of progression to diabetes. 2. Over a period of 3 years, screen in our center 30,000 general population newborns for HLA-DR,DQ genotypes associated with T1DM and enroll into the standardized prospective follow-up 500 high-risk newborns (HLA- DR3/4,DQB1*0302) and 1,200 moderate-risk newborns with no family history of TIDM. 3. Over the entire initial study period, screen in our center 1,500 newborn first-degree relatives of T1DM patients with the goal of enrolling into the standardized prospective follow-up 100 high-risk newborn relatives (HLA- DR3/4,DQBI*0302) and 100 moderate-risk newborn relatives. 4. Follow the cohorts described above until the end of the funding period and continuously (through additional competitive awards) until the age of 15 yrs to: a) further define the incidence of islet autoimmunity and diabetes by age, race/ethnicity, HLA-genotype, and family history of T1DM; b) using a case-cohort or nested case-control approach, formally evaluate candidate environmental triggers and promoters of islet autoimmunity and diabetes, e.g., early childhood diet, infections, and vaccination; c) in a very intensive follow-up from birth of the highest risk children - HLA-DR3/4,DQB1*0302 relatives carry out 'high resolution' evaluation of candidate environmental agents d) in a substudy involving pre-natally identified relatives, evaluate candidate environmental factors that may determine T1DM risk in utero. 5. To explore gene-environment interactions using combined approaches of case-control and case parent analyses. PERFORMANCESITE(S) (organization,city,state) University of Colorado Health Sciences Center, Barbara Davis Center for Childhood Diabetes Denver, Colorado KEYPERSONNEL. Seeinstructions. Usecontinuationpagesas neededto providethe requiredinformationin the formatshown below. Startwith PrincipalInvestigator.Listall other key personnelinalphabeticalorder, last namefirst. Name Organization Roleon Project Rewers, Marian J. University of Colorado P.I. Eisenbarth, George S. University of Colorado Investigator Erlich, Henry A. Roche Molecular Systems, Human Genetics Consultant Fiallo-Scharer, Rosanna University of Colorado Investigator Follensbee, Donna Independent Licensed Psychologist Consultant Gottlieb, Peter University of Colorado Investigator Lipkin, W. lan Columbia University Consultant MacKenzie, Todd University of Colorado Investigator Norris, Jill M. University of Colorado Investigator Oberste, Steven CDC, Enterovirus Reference Laboratory Consultant Pallansch, Mark CDC, Enterovirus Reference Laboratory Consultant DisclosurePermissionStatemenLApplicableto SBIR/STTROnly. See instructions. [] Yes [] No [] PHS398 (Rev.05/01) Page 2, FormPage2 [] [] Principal InvestigatodProgram Director (Last, first, middle): Rewers, Marian, J. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbe_ Face Page ....................................................................................................................................... 1 Description,

本建议书是对RFA-DK 02 -029“环境触发器类型识别联盟”的回应。 1糖尿病”。我们在该领域的经验来自年轻人糖尿病自身免疫研究（DAISY， DK32493，M.雷沃斯私家侦探7/93-6/06）。DAISY始于1993年7月，使我们能够建立两个独特的队列， 1型糖尿病（T1 DM）的发病风险是其他糖尿病患者的20倍。前瞻性随访其他地方的同类研究已经提供了有关b细胞自然史的重要信息。自身免疫和糖尿病在幼儿期，包括候选环境触发因素，但也导致了认识到明确的答案将需要大规模的合作努力，并推动了这一RFA。我们建议实现以下具体目标： 1.与其他CC和DCC合作，制定标准筛查和随访方案， 5200名一般人群新生儿和500名T1 DM患者新生儿亲属的队列， T1 DM的遗传风险目的是跟踪这些队列的胰岛自身抗体和糖尿病，直到15岁年，以确定糖尿病前期的环境触发因素和糖尿病进展的促进因素。 2.在3年的时间里，在我们的中心筛查30，000名普通人群新生儿的HLA-DR，DQ基因型与T1 DM相关，并纳入标准化前瞻性随访500例高危新生儿（HLA- DR 3/4，DQB 1 *0302）和1,200名无TIDM家族史的中度风险新生儿。 3.在整个初始研究期间，在我们的中心筛选了1，500名T1 DM患者的新生儿一级亲属，标准化前瞻性随访的目标是招募100名高危新生儿亲属（HLA- DR 3/4，DQBI*0302）和100名中度风险新生儿亲属。 4.在供资期结束前，跟踪上述队列，并持续（通过额外的竞争性奖项），直到15岁： a）通过年龄、种族/民族、HLA基因型进一步定义胰岛自身免疫和糖尿病的发病率，和 T1 DM家族史; B）使用病例队列或嵌套病例对照方法，正式评估候选环境触发因素，胰岛自身免疫和糖尿病的促进剂，例如，幼儿饮食、感染和疫苗接种; c）在从最高风险儿童-HLA-DR 3/4、DQB 1 *0302亲属出生起的非常密集的随访中，候选环境剂的“高分辨率”评价 d）在涉及出生前确定的亲属的子研究中，评估可能在子宫内确定T1 DM风险。 5.采用病例对照和病例亲本分析相结合的方法探讨基因-环境相互作用。地点（组织、城市、州）科罗拉多大学健康科学中心，芭芭拉戴维斯儿童糖尿病中心丹佛，科罗拉多关键人员。请参阅说明。需要使用第二个续页以下面所示的格式提供所需信息。从主要研究者开始，按顺序列出其他关键人员，姓在前。名称组织机构项目 Rewers，Marian J.科罗拉多大学P.I. Eisenbarth，乔治S.科罗拉多大学研究员 Erlich，亨利A. Roche Molecular Systems，人类遗传学顾问 Fiallo-Scharer，Rosanna科罗拉多大学研究员 Follensbee，Donna独立执业心理学家顾问 Gottlieb，Peter科罗拉多大学研究员 Lipkin，W.兰哥伦比亚大学顾问麦肯齐，托德科罗拉多大学研究员作者：Norris，Jill M.科罗拉多大学研究员 Oberste，Steven CDC，肠道病毒参考实验室顾问 Pallansch，Mark CDC，肠道病毒参考实验室顾问披露许可声明L仅适用于SBIR/STTR。参见说明。[]是[]否 [] PHS 398（版本05/01）第2页，表格第2页[] []首席研究员项目主任（最后，第一，中间）：Rewers，Marian，J. 主要研究者/项目负责人的姓名必须在打印页和续页的顶部提供。研究资助目录页码_ 首页...... 1 产品描述：