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: 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
• 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

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) 的特点通常是进行性 β 细胞衰竭，导致血糖控制不佳、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这种 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，CD44 是一种与 T2DM 发病机制密切相关的分子，它是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多糖。我们已经确定了 CD44 及其主要配体透明质酸 (HA) 在与 T2DM 相关的 β 细胞衰竭中的新作用。我们最近报道，在 T2DM 中，CD44 和 HA 均因高血糖和炎症细胞因子而全身增加。与此一致的是，非糖尿病受试者中的胰岛 HA 和 CD44 水平可以忽略不计，但在患有 T2DM 的人类尸体捐献者中却含量丰富。类似的发现也出现在该疾病的 db/db 小鼠模型中。此外，用β细胞毒素链脲佐菌素治疗小鼠可增强β细胞HA和CD44的产生。这些数据表明，胰岛 HA 和 CD44 作为对损伤的急性反应而上调，并且它们在 T2DM 中的长期表达可能具有致病性。我们的初步数据强烈表明 HA 和 CD44 与 T2DM 特征的 β 细胞衰竭有关。用 4-甲基伞形酮 (4-MU)（一种口服 HA 合成抑制剂）治疗 db/db 小鼠，可清除胰岛 HA 沉积物并促进这些动物的胰岛素产生。同样，CD44-/-.db/db 小鼠尽管病态肥胖，但不会损失 β 细胞质量或患上糖尿病。此外，4-MU 治疗和 CD44 缺失都可以预防低剂量链脲佐菌素。总之，这些数据表明 HA 和 CD44 在 β 细胞衰竭中起决定性作用。与此一致，我们已经确定了 HA 和 CD44 在成纤维细胞生长因子 21 (FGF21) 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) 信号传导的反应较差，尤其是在 HA 存在的情况下。然而，T2DM 中 β 细胞衰竭的潜在机制及其贡献尚不清楚。根据我们令人兴奋的初步数据，我们假设 CD44 通过抑制 FGF21 反应而导致 T2DM 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 T2DM 中的 β 细胞衰竭。为了检验这一假设，在目标 1 中，我们将定义 CD44 在 T2DM β 细胞丢失中的作用。在目标 2 中：我们将定义 CD44 介导的对 β 细胞 FGF21 反应的影响所涉及的机制。最后，在目标 3 中，我们将开发针对 HA/CD44 的疗法，以保护人类 β 细胞量。总之，这些目标有可能揭示 T2DM 发展的基本新途径，并引入改善 T2DM 血糖控制的新疗法。