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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.