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

• 批准号: 10578727
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-22 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578727
• 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; 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

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.

慢性2型糖尿病（T2DM）通常以进行性β细胞衰竭为特征，导致血糖控制不良、胰岛素依赖和更严重的糖尿病并发症。虽然高血糖和炎症与β细胞死亡有关，但其潜在机制尚不清楚。全基因组关联研究表明，与T2DM发病密切相关的一个分子是CD44，这是一种细胞表面蛋白聚糖，介导细胞与细胞外基质之间的相互作用。我们已经确定了CD44及其主要配体透明质酸（HA）在T2DM相关β细胞衰竭中的新作用。我们最近报道了CD44和HA在T2DM患者高血糖和炎症细胞因子反应中全身性升高。与此一致的是，胰岛HA和CD44水平在非糖尿病患者中可以忽略不计，但在患有2型糖尿病的人类尸体供体中却很丰富。在该疾病的db/db小鼠模型中也有类似的发现。此外，用β细胞毒素链脲佐菌素治疗小鼠可以增强β细胞产生HA和CD44。这些数据表明，胰岛HA和CD44作为对损伤的急性反应而上调，它们在T2DM中的长期表达可能是致病的。我们的初步数据强烈暗示HA和CD44与T2DM的β细胞衰竭有关。口服HA合成抑制剂4- methylumbellliferone （4-MU）治疗db/db小鼠，清除这些动物的胰岛HA沉积并促进胰岛素生成。类似地，CD44-/-.db/db小鼠尽管是病态肥胖，但也不会失去β细胞团或发展为糖尿病。此外，4-MU处理和CD44缺失都对低剂量链脲佐菌素具有保护作用。总之，这些数据指出了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）的反应中的作用，FGF21是β细胞功能和稳态的关键调节因子。表达CD44的β细胞对fgf21介导的FGF受体1 （FGFR1）信号的反应较弱，特别是在HA存在的情况下。然而，潜在的机制及其对2型糖尿病β细胞衰竭的贡献尚不清楚。根据我们令人兴奋的初步数据，我们假设CD44通过抑制FGF21反应来驱动T2DM中β细胞衰竭。此外，我们建议4-MU，已经被批准的药物，可以重新用于预防2型糖尿病的β细胞衰竭。为了验证这一假设，在目的1中，我们将定义CD44在T2DM中β细胞损失中的作用。在目标2中，我们将定义cd44介导的β细胞FGF21反应的机制。最后，在Aim 3中，我们将开发靶向HA/CD44的疗法来保护人类β细胞团。总之，这些目标有可能揭示T2DM发展的基本新途径，并引入新的治疗方法，改善T2DM患者的血糖控制。