Role of pericytes in pancreatic islet fibrosis

周细胞在胰岛纤维化中的作用

• 批准号: 9224509
• 负责人: Joana Almaca
• 金额: $ 12.93万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224509
• 关键词: Affect; Age; Aging; Architecture; Behavior; Beta Cell; Biology; Blast Cell; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Cell Death; Cells; Collagen; Data; Defect; Deposition; Diabetes Mellitus; Diabetic mouse; Disease; Endocrine; Endothelial Cells; Engineering; Exposure to; Extracellular Matrix Proteins; Eye; FRAP1 gene; Fibrosis; Fluorescence; Functional disorder; Generations; Goals; Green Fluorescent Proteins; Growth; Health; Human; Hyperinsulinism; Image; Impairment; In Vitro; Incidence; Insulin; Insulin Receptor; Insulin Resistance; Islet Cell; Islets of Langerhans; Knowledge; Lead; Lesion; Measures; Mission; Modeling; Mus; Myofibroblast; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Organism; Outcome; Pancreas; Pathogenesis; Pathologic; Pericytes; Pharmacology; Phenotype; Play; Protein Kinase; Proteins; Receptor Activation; Research; Research Proposals; Role; Signal Transduction; Sirolimus; Smooth Muscle; Staining method; Stains; Structure; Testing; Tissues; Transgenic Mice; Transplantation; United States National Institutes of Health; Vascular Diseases; Work; age related; aged; base; blood glucose regulation; capillary; diabetic; eye transplantation; in vivo; insulin secretion; insulin signaling; interstitial; islet; mouse model; non-invasive imaging; optogenetics; tool; transdifferentiation

Abstract Fibrosis is the most frequent lesion in the islets of type 2 diabetics (T2D) and contributes to the age-dependent impairment of islet function. Defects in islet vasculature compromise exchanges between the endocrine cells and the blood, disrupt islet architecture and ultimately lead to endocrine cell death. An important component of the vasculature is the pericyte, a contractile smooth muscle-like cell that wraps small blood vessels. In different organs, pericytes have been shown to differentiate into myofibroblasts, leading to fibrosis and organ dysfunction. Whether islet pericytes also contribute to the profibrotic myofibroblast pool that causes islet fibrosis observed during aging and T2D has not been determined. The long-term goal of this proposal is to understand the role of vascular dysfunction in aging and diabetes. The objectives of this project are to determine how the islet pericyte phenotype changes during insulin resistant states (such as aging and T2D) and what causes the changes, using a combination of in vitro and in vivo approaches. The central hypothesis is that, during aging or T2D, the excessive exposure to insulin exacerbates signaling through the mammalian target of rapamycin (mTOR) in pericytes, which makes them differentiate into myofibroblasts. In our model, as hyperinsulinemia develops to compensate for insulin resistance, islet pericytes are exposed to higher levels of insulin. Insulin overactivates mTOR signaling in pericytes, which favors their differentiation into myofibroblasts and proliferation of these profibrotic cells. The rationale for the proposed research is that the results will make a lasting impact on our understanding of the role of the pericyte in islet biology. If the hypothesis is correct, it would demonstrate the fundamental contribution of pericytes to islet fibrosis and diabetes pathogenesis. The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of fundamental knowledge about the nature and behavior of living systems. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) Identify age- and diabetes-induced changes in the phenotype of the islet pericyte; 2) Determine the role of mTOR-dependent insulin signaling in pericyte transdifferentiation. Under the first aim, we will examine changes in the pericyte phenotype in aged and T2D mouse and human islets, and directly visualize the phenotypic transition from pericytes to myofibroblasts in vivo. Under the second aim, we will determine if direct in vitro and in vivo stimulation of islet pericytes with insulin triggers a pro-fibrotic myofibroblast-like phenotype. We will further manipulate mTOR signaling in pericytes in vivo and measure the effects on vascular function and glucose homeostasis. The proposed research is significant because pericytes can be targeted to limit the generation of myofibroblasts and interstitial collagen accumulation during islet fibrosis that accompanies aging and T2D. Importantly, these studies have the potential to impact the way diabetes is treated.

摘要 纤维化是2型糖尿病（T2 D）胰岛中最常见的病变，并导致年龄依赖性糖尿病。 胰岛功能受损。胰岛血管系统的缺陷损害了内分泌细胞之间的交换 和血液，破坏胰岛结构，并最终导致内分泌细胞死亡。的重要组成部分 脉管系统是周细胞，一种包裹小血管的收缩性平滑肌样细胞。在不同 在器官中，周细胞已显示分化成肌成纤维细胞，导致纤维化和器官损伤。 功能障碍胰岛周细胞是否也有助于导致胰岛细胞增殖的促纤维化肌成纤维细胞池 在老化和T2 D期间观察到的纤维化尚未确定。该提案的长期目标是 了解血管功能障碍在衰老和糖尿病中的作用。该项目的目标是 确定胰岛素抵抗状态（如衰老和T2 D）期间胰岛周细胞表型如何变化 以及是什么导致了这些变化，结合体外和体内的方法。核心假设 在衰老或T2 D期间，过度暴露于胰岛素会加剧通过哺乳动物细胞的信号传导， 雷帕霉素靶点（mTOR）在周细胞，使他们分化成肌成纤维细胞。在我们的模型中， 高胰岛素血症发展以补偿胰岛素抵抗，胰岛周细胞暴露于更高水平的胰岛素， 胰岛素胰岛素过度激活周细胞中的mTOR信号传导，这有利于它们分化为肌成纤维细胞 以及这些促纤维化细胞的增殖。拟议研究的基本原理是，研究结果将使 对我们理解周细胞在胰岛生物学中的作用产生了持久的影响。如果假设是正确的， 将证明周细胞对胰岛纤维化和糖尿病发病机制的基本贡献。的 因此，拟议的研究与NIH的使命有关，NIH的使命是追求基本的 了解生命系统的性质和行为。在强大的初步数据的指导下，我们的中央 将通过追求两个具体目标来检验这一假设：1）确定年龄和糖尿病引起的 胰岛周细胞的表型; 2）确定mTOR依赖性胰岛素信号传导在周细胞中的作用 转分化在第一个目标下，我们将研究老年人和T2 D患者周细胞表型的变化。 小鼠和人类胰岛，并直接可视化从周细胞到肌成纤维细胞的表型转变， vivo.在第二个目标下，我们将确定是否直接在体外和体内刺激胰岛周细胞， 胰岛素触发促纤维化成肌纤维细胞样表型。我们将进一步操纵mTOR信号， 在体内测量周细胞的生长，并测量对血管功能和葡萄糖稳态的影响。拟议 研究是重要的，因为周细胞可以被靶向以限制肌成纤维细胞的产生， 胰岛纤维化期间的间质胶原蛋白积聚，伴随着衰老和T2 D。重要的是这些 研究有可能影响糖尿病的治疗方式。