Evaluation of signals mediating beta-cell regeneration

介导 β 细胞再生的信号评估

基本信息

批准号：
8883807
负责人：
FARZAD ESNI
金额：
$ 33.63万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883807
关键词：
Address Adoptive Transfer Adult Apoptotic Area Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biology Blood Glucose CD3 Antigens Cell Proliferation Cell Therapy Cells Coculture Techniques Diabetes Mellitus Elements Ensure Environment Evaluation Experimental Models Failure Future Generations Genetic Predisposition to Disease Goals Human Immunogenetics Immunosuppressive Agents Immunotherapy In Vitro Inbred NOD Mice Inflammation Injury Insulin Insulin-Dependent Diabetes Mellitus Mediating Modeling Molecular Profiling Mus Natural regeneration Pancreas Patients Phenotype Physiological Predisposition Publishing Recovery Reporting Research Research Personnel Role Signal Transduction Syndrome Testing Therapeutic Work design diabetic differential expression feeding in vivo in vivo regeneration islet macrophage meetings monocyte peripheral blood prevent public health relevance regenerative release factor repaired research study

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes is a syndrome defined by high blood glucose levels caused by reduction in number of insulin producing cells, thus a cure for diabetes should entail replacement of ß-cells. There is a genetic predisposition for autoimmune susceptibility regarding macrophage phenotype in NOD mice and human T1D-patients, which contributes to persistence of inflammation, and ß-cell destruction. Here, we provide evidence that macrophages are important elements of pancreatic regeneration in general, and ß-cell generation in particular. Furthermore, we demonstrate that macrophages isolated from the NOD strain have an inherent inability to induce ß-cell generation. In this proposal, we will test the central hypothesis that Type1 diabetes is the combined effect of autoimmunity and the inability of macrophages to generate a cellular phenotype important for ß-cell regeneration. The experimental models described in this proposal will allow us to further study the macrophage-dependent ß-cell proliferation in mice (specific aims 1), to evaluate the ability of human-derived macrophages to induce ß- cell replication (specific aims 2), and to identify putative factors released by macrophages that are necessary for human ß-cell generation (specific aims 3). Immune therapy significantly reduces the autoimmune-associated ß-cell proliferation. Thus, additional therapeutic approaches that would stimulate ß-cell regeneration in the absence of autoimmune destruction may be needed for recovery of ß-cell mass. As a potential cell therapeutic approach, macrophages generated from patient's monocytes could be reprogrammed to promote ß-cell regeneration. This work is a high priority area as it is directly applicable to our full understanding and potential treatment of T1D.

描述（由应用提供）：1型糖尿病是一种由胰岛素生产细胞数量减少引起的高血糖水平定义的综合征，因此糖尿病的治愈应需要替换β细胞。在NOD小鼠和人类T1D患者中，对巨噬细胞表型的自身免疫性易感性存在遗传易感性，这有助于炎症的持久性和ß细胞破坏。在这里，我们提供的证据表明巨噬细胞是胰腺再生的重要要素，尤其是β细胞产生。此外，我们证明了从NOD菌株中分离出来的巨噬细胞具有遗传能力诱导ß细胞产生。在此提案中，我们将检验一个中心假设：1型糖尿病是自身免疫性的综合作用，而巨噬细胞无法产生对ß细胞再生很重要的细胞表型。该提案中描述的实验模型将使我们能够进一步研究小鼠中巨噬细胞依赖的β细胞增殖（特定目的1），以评估人类衍生的人的能力巨噬细胞诱导ß细胞复制（特定目的2），并确定巨噬细胞释放的推定因素，这些因素是人β-细胞产生所必需的（特定目的3）。免疫治疗可显着降低自身免疫相关的ß细胞增殖。这是在没有自身免疫性破坏的情况下恢复β-细胞质量可能需要刺激β细胞再生的其他治疗方法。作为一种潜在的细胞治疗方法，可以重编程从患者的单核细胞产生的巨噬细胞以促进β细胞再生。这项工作是一个高优先级领域，因为它直接适用于我们对T1D的全面理解和潜在处理。