The Role of Hyaluronan and CD44 in the Pathogenesis of Type 2 Diabetes

透明质酸和 CD44 在 2 型糖尿病发病机制中的作用

基本信息

批准号：
10359164
负责人：
Paul L Bollky
金额：
$ 39.58万
依托单位：
STANFORD UNIVERSITY
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：
2020-04-22 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359164
关键词：
4-methylumbelliferone Acute Animals Beta Cell CD44 gene Cadaver Cell Line Cell Survival Cell physiology Cell surface Chronic Complications of Diabetes Mellitus Data Dependence Deposition Development Diabetes Mellitus Disease Disease model Dose Engineering Extracellular Matrix FGF21 gene Failure Fibroblast Growth Factor Receptors Functional disorder Homeostasis Homodimerization Human Hyaluronan Hyperglycemia Inflammation Inflammatory Insulin Islets of Langerhans Transplantation Length Ligands Light Mediating Modeling Morbid Obesity Mus Non-Insulin-Dependent Diabetes Mellitus Oral Organ Donor Pancreas Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Preparations Phosphotransferases Production Proteoglycan Reporting Role SCID Mice Signal Transduction Streptozocin Stress Testing Therapeutic Tissues Toxin cellular transduction cytokine db/db mouse diabetic diet-induced obesity experimental study fibroblast growth factor 21 genetic manipulation genome wide association study glycemic control improved in vivo inhibitor islet loss of function mouse model non-diabetic novel preservation prevent repository response response to injury targeted treatment therapy development treatment strategy

项目摘要

PChronic Type 2 Diabetes Mellitus (T2DM) is often characterized by progressive β-cell failure, leading to poor glycemic control, insulin dependence, and more severe diabetic complications. While hyperglycemia and inflammation are implicated in this β-cell demise, the underlying mechanisms are unclear. One molecule strongly implicated in T2DM pathogenesis by genome-wide association studies is CD44, a cell-surface proteoglycan that mediates interactions between cells and the extracellular matrix. We have identified a novel role for CD44 and its primary ligand hyaluronan (HA) in the β-cell failure associated with T2DM. We recently reported that both CD44 and HA are increased systemically in response to hyperglycemia and inflammatory cytokines in T2DM. Consistent with this, islet HA and CD44 levels are negligible in non-diabetic subjects but abundant in human cadaveric donors with T2DM. Similar findings are present in the db/db mouse model of the disease. Further, treatment of mice with the β-cell toxin streptozotocin enhances β-cell production of both HA and CD44. These data suggest that islet HA and CD44 are upregulated as an acute response to injury and that their prolonged expression in T2DM may be pathogenic. Our preliminary data strongly implicate HA and CD44 in the β-cell failure that characterizes T2DM. Treatment of db/db mice with 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, clears islet HA deposits and promotes insulin production in these animals. Similarly, CD44-/-.db/db mice do not lose β-cell mass or develop diabetes despite being morbidly obese. Moreover, both 4-MU treatment and deletion of CD44 are protective against low-dose streptozotocin. Together, these data point to decisive roles for HA and CD44 in β-cell failure. Consistent with this, we have identified a role for HA and CD44 in responses to fibroblast growth factor 21 (FGF21), a key regulator of β-cell function and homeostasis. β-cells that express CD44 are less responsive to FGF21-mediated FGF receptor 1 (FGFR1) signaling, particularly in the presence of HA. However, the underlying mechanisms and their contribution to β-cell failure in T2DM are unknown. In light of our exciting preliminary data, we hypothesize that CD44 drives β-cell failure in T2DM via inhibition of FGF21 responses. Further, we propose that 4-MU, already an approved drug, could be repurposed to prevent β-cell failure in T2DM. To test this hypothesis, in Aim 1 we will define the role of CD44 in β-cell loss in T2DM. In Aim 2: we will then define the mechanisms involved in CD44-mediated effects on β-cell FGF21 responses. Finally, in Aim 3 we will develop therapies that target HA/CD44 to preserve human β-cell mass. Together, these Aims have the potential to reveal fundamental new pathways underlying the development of T2DM and to introduce novel treatments that will improve glycemic control in T2DM.

Pchronic 2型糖尿病（T2DM）通常以进行性β细胞衰竭，导致血糖控制不良，胰岛素依赖性和更严重的糖尿病并发症。尽管在这种β细胞灭绝中实施了高血糖和炎症，但尚不清楚潜在的机制。通过基因组关联研究与T2DM发病机理的一种分子是CD44，这是一种细胞表面蛋白聚糖，可介导细胞与细胞外基质之间的相互作用。我们已经确定了与T2DM相关的β细胞衰竭中CD44及其主要配体透明质酸（HA）的新作用。我们最近报告说，CD44和HA在T2DM中对高血糖和炎性细胞因子的响应均全身增加。与此相一致，在非糖尿病受试者中，胰岛和CD44水平可以忽略不计，但在具有T2DM的人尸体供体中丰富。该疾病的DB/DB小鼠模型中也提出了类似的发现。此外，用β细胞毒素链蛋白酶治疗小鼠可增强HA和CD44的β细胞产生。这些数据表明，胰岛HA和CD44是对损伤的急性反应而更新的，并且它们在T2DM中的延长表达可能是致病性的。我们的初步数据强烈暗示HA和CD44在特征T2DM的β细胞故障中。用HA合成的口服抑制剂（4-mu）处理DB/DB小鼠的DB/DB小鼠清除了HA沉积物并促进这些动物中的胰岛素产生。同样，CD44 - / - 。dB/db小鼠不会失去β细胞质量或发展糖尿病是浓汤或糖尿病的质量或发展糖尿病，尽管病态肥胖。此外，对低剂量链球菌素的4-MU治疗和CD44的缺失均受到保护。这些数据共同指出了HA和CD44在β细胞衰竭中的决定性作用。与此一致，我们已经确定了HA和CD44在对成纤维细胞生长因子21（FGF21）的响应中的作用，这是β细胞功能和稳态的关键调节剂。表达CD44的β细胞对FGF21介导的FGF受体1（FGFR1）信号的反应较小，尤其是在HA存在的情况下。但是，尚不清楚基本机制及其对T2DM中β细胞衰竭的贡献。鉴于我们令人兴奋的初步数据，我们假设CD44通过抑制FGF21响应来驱动T2DM中的β细胞衰竭。此外，我们建议可以重新使用4-MU，以防止T2DM中的β细胞衰竭。为了检验这一假设，在AIM 1中，我们将定义CD44在T2DM中β细胞损失中的作用。在AIM 2中：然后，我们将定义参与CD44介导的对β细胞FGF21响应的作用的机制。最后，在AIM 3中，我们将开发靶向HA/CD44以保留人β细胞质量的疗法。这些目标共同揭示了T2DM开发的基本新途径，并引入了可以改善T2DM血糖控制的新型治疗方法。