Modulating the senescence secretome to block progression of T1D

调节衰老分泌蛋白组以阻止 T1D 的进展

基本信息

批准号：
9886134
负责人：
Anil Bhushan
金额：
$ 50.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886134
关键词：
Address Affect Antigen Presentation Autoimmune Diseases BCL2 gene Beta Cell Binding Bromodomain Cell Aging Cell Communication Cells Cellular Metabolic Process Cellular Stress Response Characteristics Chemotaxis Chromatin DNA Damage DNA Double Strand Break DNA Repair DNA Repair Enzymes DNA Repair Pathway Data Dendritic Cells Development Diabetes Mellitus Disease Disease model Double Strand Break Repair Environment Extracellular Matrix Gene Activation Genes Genetic Transcription Goals Human Hyperglycemia Immune Immune response Immunologic Surveillance Inbred NOD Mice Inflammatory Insulin-Dependent Diabetes Mellitus Laboratories Mediator of activation protein Morphology Mus Natural History Nucleotides Organ Pathogenesis Patients Pharmaceutical Preparations Phenotype Play Poly(ADP-ribose) Polymerases Process Proteins Reporter Resolution Role Signal Transduction Structure of beta Cell of islet Therapeutic Transcriptional Activation Work base cell type chromatin remodeling extracellular vesicles humanized mouse immunoregulation in vivo inhibitor/antagonist islet mimetics monocyte mouse model next generation sequencing novel therapeutic intervention paracrine prevent senescence therapeutic development transplant model vesicular release

项目摘要

Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. We have discovered that during T1D, pancreatic beta cells in mice and human acquire a fate reminiscent of senescence associated secretory phenotype (SASP). Senescent beta cells can remodel the islet environment in a paracrine manner by promoting bystander senescence and immune surveillance. We have developed drugs that selectively eliminated SASP beta cells without altering the abundance of the major immune cell types involved in the disease. Significantly, elimination of SASP beta cells halted progression of beta cell destruction and was sufficient to prevent diabetes (Thompson et al, 2019 Cell Metabolism in press). In this proposal, we address how DNA damage leads beta cells to acquire a senescent fate in a T1D setting and the role of DNA repair processes in inducing DNA damage. Such understanding will be important to establish how we can direct DNA repair pathways to eliminate or dampen the senescence of beta cells. We also investigate the transcriptional and chromatin changes in senescent beta cells and whether we can target key regulators to dampen the senescence phenotype. Finally, we explore whether extracellular vesicles from senescent beta cells are involved in cell-cell communication and transmitting signals to regulate the immune response. Such an approach will broaden upon our new finding on beta cell senescence in T1D and provide new direction to therapeutic development.

1型糖尿病是一种器官特异性的自身免疫性疾病，其特征是由于胰腺β细胞的进行性丧失而导致高血糖。我们发现，在T1D期间，小鼠的胰腺β细胞和人类获得了让人联想到衰老相关的分泌表型（SASP）的命运。衰老的β细胞可以通过促进旁观者衰老和免疫监测来以旁分泌方式重塑胰岛环境。我们开发了有选择地消除SASPβ细胞的药物，而不会改变疾病中涉及的主要免疫细胞类型的丰度。值得注意的是，消除SASPβ细胞停止了β细胞破坏的进展，足以预防糖尿病（Thompson等，2019年印刷中的细胞代谢）。在此提案中，我们解决了DNA损伤如何导致β细胞在T1D设置中获得衰老的命运以及DNA修复过程在诱导DNA损伤中的作用。这种理解对于确定如何指导DNA修复途径以消除或抑制β细胞的衰老很重要。我们还研究了衰老β细胞中的转录和染色质变化，以及我们是否可以靶向关键调节剂以抑制衰老表型。最后，我们探索来自衰老β细胞的细胞外囊泡是否参与细胞 - 细胞通信和传输信号以调节免疫反应。这种方法将扩大我们关于T1D中β细胞衰老的新发现，并为治疗性发育提供了新的方向。