Environmental Causes of Type 1 Diabetes

本提案是对RFA-DK02-029《环境触发因素类型识别联合会》的响应 我们在这一领域的经验来自于青少年糖尿病自身免疫研究(黛西， DK32493，M.Rewers，P.I.，7/93-6/06)。黛西开始于1993年7月，让我们建立了两个独特的队列 年幼的儿童患1型糖尿病(T1 DM)的风险增加20倍。这些项目的预期后续行动 其他地方的类似研究已经提供了关于b细胞自然历史的重要信息。 自身免疫和儿童早期糖尿病，包括候选的环境触发因素，但也导致了 认识到最终的答案将需要大规模的合作努力，并推动了这一RFA。我们是 提议解决以下具体目标： 1.与其他CCS和DCC合作，制定标准筛查和后续方案，以建立 5200名普通人群新生儿和500名T1 DM新生儿亲属高中组队列分析 T1 DM的遗传风险。其目的是跟踪这些胰岛自身抗体和糖尿病的队列，直到15岁。 为了找出糖尿病前期的环境诱因和糖尿病进展的促进剂，我们已经进行了数年的研究。 2.用3年时间对3万名普通人群新生儿进行人类白细胞抗原-DR、DQ基因分型筛查 并纳入标准化前瞻性随访500例高危新生儿(人类白细胞抗原-1)。 DR3/4，DQB1*0302)和1200例无TIDM家族史的中危新生儿。 3.在整个初始研究期间，在我们中心筛查1,500名患有糖尿病的新生儿一级亲属 纳入标准化前瞻性随访100名高危新生儿亲属(人类白细胞抗原-1)的目标。 DR3/4、DQBI*0302)和100名中危新生儿亲属。 4.遵循上述队列，直到资助期结束，并持续(通过额外的 竞赛奖项)至15岁以下： A)进一步按年龄、种族/民族、人类白细胞抗原基因型别和 T1 DM家族史； B)采用病例队列或嵌套病例对照方法，正式评估候选环境诱因，并 胰岛自身免疫和糖尿病的促进者，例如儿童早期饮食、感染和疫苗接种； C)在高危儿童--人类白细胞抗原--DR3/4出生后的一次非常密集的跟踪中，DQB1*0302的亲属进行了 对候选环境制剂的“高分辨率”评价 D)在一项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的风险。 5.采用病例对照和病例亲子分析相结合的方法探讨基因与环境的交互作用。 Performmanceite(S)(组织、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 科罗拉多州丹佛市 凯佩尔松内尔。请参阅说明。使用以下所示的格式提供所需信息所需的二次使用页面。 从首席调查员开始。按字母顺序列出其他关键人员，姓氏在前。 名称组织角色项目 科罗拉多州立大学玛丽安·J·赖尔斯，P.I. 科罗拉多大学乔治·S·艾森巴特研究员 亨利·A·罗氏分子系统，人类遗传学顾问 Fiallo-Scharer，科罗拉多大学罗莎娜大学研究员 Follensbee，唐娜独立执业心理学家顾问 Gottlieb，科罗拉多彼得大学研究员 利普金，W.lan哥伦比亚大学顾问 麦肯齐，科罗拉多托德大学研究员 科罗拉多大学研究员 Oberste，Steven CDC，肠道病毒参考实验室顾问 马克·帕兰施，肠道病毒参考实验室顾问 DisclosurePermissionStatemenLApplicableto SBIR/STTROnly(解除权限状态可应用于SBIR/STTROnly)。请参阅说明。[]是[]否 []PHS398(05/01版)第2页，表格2[] []首席调查项目主任(最后、第一、中间)：Rewers，Marian，J. 必须在每张打印页和每张续页的顶部提供首席调查员/项目主任的姓名。 研究补助金 目录 页码_ 主页.......................................................................................................................1 描述，

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,