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.

P慢性2型糖尿病（T2 DM）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。虽然高血糖症和炎症与这种β细胞死亡有关，但其潜在机制尚不清楚。通过全基因组关联研究，一种与T2 DM发病机制密切相关的分子是CD 44，一种介导细胞与细胞外基质之间相互作用的细胞表面蛋白聚糖。我们已经确定了CD 44及其主要配体透明质酸（HA）在与T2 DM相关的β细胞衰竭中的新作用。我们最近报道，CD 44和HA在2型糖尿病中对高血糖和炎性细胞因子的反应中全身性增加。与此一致，非糖尿病受试者中的胰岛HA和CD 44水平可忽略不计，但在T2 DM人尸体供体中含量丰富。在db/db小鼠疾病模型中也存在类似的发现。此外，用β-细胞毒素链脲佐菌素处理小鼠增强HA和⑶ 44两者的β-细胞产生。这些数据表明，胰岛HA和CD 44作为对损伤的急性反应而上调，并且它们在T2 DM中的长期表达可能是致病性的。我们的初步数据强烈暗示HA和CD 44在β细胞衰竭中是T2 DM的特征。用HA合成的口服抑制剂4-甲基伞形酮（4-MU）治疗db/db小鼠，清除胰岛HA沉积并促进这些动物中的胰岛素产生。类似地，CD 44-/-.db/db小鼠尽管病态肥胖，但不损失β细胞质量或发展糖尿病。此外，4-MU治疗和CD 44缺失均对低剂量链脲佐菌素具有保护作用。总之，这些数据表明HA和CD 44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CD 44在响应成纤维细胞生长因子21（FGF 21）中的作用，FGF 21是β细胞功能和稳态的关键调节因子。表达⑶ 44的β细胞对FGF 21介导的FGF受体1（FGFR 1）信号传导的响应性较低，特别是在HA存在下。然而，T2 DM的潜在机制及其对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CD 44通过抑制FGF 21应答驱动T2 DM中的β细胞衰竭。此外，我们建议已经批准的药物4-MU可以重新用于预防T2 DM中的β细胞衰竭。为了验证这一假设，在目标1中，我们将定义CD 44在T2 DM β细胞丢失中的作用。在目标2中：我们将定义CD 44介导的对β细胞FGF 21反应的影响所涉及的机制。最后，在目标3中，我们将开发靶向HA/CD 44的疗法以保留人β细胞群。总之，这些目标有可能揭示T2 DM发展的基本新途径，并引入改善T2 DM血糖控制的新型治疗方法。