Determining the rap1b signaling pathway to integrin activation in platelets

确定血小板中整合素激活的 rap1b 信号通路

基本信息

批准号：
7332818
负责人：
Luis Alberto Paniagua
金额：
$ 3.21万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2013-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7332818
关键词：
Adoptive Transfer Age Animal Model Animals Appendix Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Bioinformatics Blood Platelets CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Child Congenic Strain Cytotoxic T-Lymphocytes Daily Data Dependence Dependency Development Diabetes Mellitus Disease Disease Progression Eotaxin Event Exhibits Fellowship Functional disorder Gene Expression Genes Genetic Genomics Health Human Immune Immune System Diseases Immune system In Vitro Inbred WF Rats Incidence Individual Infiltration Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Integrins Interleukin-1 Interleukins Invasive Islets of Langerhans Life Localized Major Histocompatibility Complex Maps Mediating Mediator of activation protein Mutation Onset of illness Pancreas Pathogenesis Pathway Analysis Peripheral Pharmaceutical Preparations Population Predisposition Rat Strains Rattus Recruitment Activity Regulation Relative (related person)Research Risk Role Sampling Signal Pathway Signal Transduction Staining method Stains Stress T-Lymphocyte Testing Time Tissues cell type chemokine congenic day diabetic eosinophil functional genomics human subject in vivo inhibitor/antagonist insight islet lymph nodes mast cell non-diabetic prevent response

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic ¿ cells and results in life-long dependency on daily insulin injection. Epidemiological data show that T1DM incidence is rising by 2-3% per year while onset is occurring at an earlier age. Since acquisition of relevant immune tissues from prediabetic children is nearly impossible, we have used congenic derivatives of the BioBreeding (BB) rat. The lymphopenic DRIyp/lyp animal develops spontaneous T1DM, whereas the DR+/+ does not. Evidence points to disease progression in BB rats being dependent on the absence of natural regulatory T (nTreg) cells. T1DM in BB rats also involves cytotoxic T cells, since their depletion is protective. Our preliminary studies show that BB rats are predisposed to T1 DM in that pancreatic ¿ cells of both DRIyp/lyp and DR+/+ strains recruit immune cells through expression of eotaxin, an eosinophil and mast cell recruiting chemokine, as well as interleukin 1¿ prior to insulitis in the DRIyp/lyp rat. Gene expression studies of prediabetic pancreatic lymph nodes (PLN) have shown that mast cells are terminally activated in DRIyp/lyp animals versus.negatively regulated in DR+/+ animals. We have successfully delayed T1DM in DRIyp/lyp rats with two different mast cell inhibiting drugs, confirming a pathogenic role for mast cells. Thus, we propose that nTreg cells in the DR+/+ rat can maintain the islet health by a peripheral regulatory mechanism, whereas in the absence of nTreg cells, DRIyp/lyp animals spontaneously progress to T1DM. We hypothesize that in the BB rat, innate immune cells mediate islet destruction unless nTreg cells prevent their mobilization. We will test our hypotheses through the following aims: 1) Temporally and spatially dissect the activities of nTreg cells during the prediabetic period at day 30 (prior to islet eotaxin signaling), day 40 (prior to insulitis), day 50 (early insulitis) and day 60 (late insulitis, pre-onset) using a combination of functional genomics and histological approaches. 2) Validate Aim 1 observations through in vitro and in vivo studies that characterize the action of nTreg on CD8 and CD4 T cells as well as innate cells. A role for mast cells in initiating and/or amplifying autoimmunity in T1DM has only recently been defined. These studies will utilize genomic, bioinformatic, histological, and immunological approaches to elucidate the relationship between innate cells and nTreg cells. This integrated approach will help us better understand how mast cells and nTreg cells interact and has the potential to establish a new paradigm for immune regulation, thus opening new insights into immune disease.

描述（通过应用程序提供）：1型糖尿病（T1DM）是通过自身免疫性破坏胰腺»细胞而产生的，并导致对每日胰岛素注射的终身依赖。流行病学数据表明，T1DM的发病率每年增加2-3％，而发病率在较早的年龄。由于几乎不可能从糖尿病儿童中获取相关的免疫组织，因此我们使用了生物培养（BB）大鼠的先天衍生物。淋巴细胞减少型DRIYP/LYP动物开发项目赞助T1DM，而DR+/+却没有。证据表明，BB大鼠的疾病进展取决于缺乏自然调节t（NTREG）细胞。 BB大鼠中的T1DM也涉及细胞毒性T细胞，因为其部署受到保护。我们的初步研究表明，在Driyp/Lyp和Dr+/+条纹的细胞中，BB大鼠易于T1 DM，通过表达嗜酸性嗜酸性粒细胞和肥大细胞募集趋化因子和interleukin interleukin，以及interleukin of interleukin of insulukin，以及interleukin of insulukin in driyp/lip lyp lyp lyp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp ryp。糖尿病前胰腺淋巴结（PLN）的基因表达研究表明，在DRIYP/LYP动物中，肥大细胞在DR+/+动物中进行了终止激活。我们成功地延迟了DRIYP/LYP大鼠的T1DM，其中有两个不同的肥大细胞抑制药物，从而证实了肥大细胞的致病作用。这就是我们提出的，DR+/+大鼠中的NTreg细胞可以通过外围调节机制维持胰岛健康，而在没有NTREG细胞的情况下，DRIYP/LYP动物在赞助下发展为T1DM。我们假设在BB大鼠中，先天免疫细胞介导胰岛破坏，除非NTREG细胞阻止其动员。我们将通过以下目的测试我们的假设：1）在第30天（胰岛Eotaxin信号之前），第40天（胰岛素之前），第50天（早期胰岛素）和第60天（早期胰岛素）和第60天（早期的胰岛素，预胰岛素，预胰岛素，预疗法）使用功能性基因组的方法和历史学上的方法，在时间和空间上剖析了NTREG细胞的活性。 2）通过体外和体内研究来验证目标1观察，这些研究表征了NTREG对CD8和CD4 T细胞以及先天细胞的作用。直到最近才定义了肥大细胞在T1DM中启动和/或扩增自身免疫性的作用。这些研究将利用基因组，生物信息学，组织学和免疫学方法来阐明先天细胞与NTREG细胞之间的关系。这种综合方法将有助于我们更好地了解肥大细胞和NTREG细胞如何相互作用，并有可能为免疫调节建立新的范式，从而为免疫疾病提供新的见解。