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：
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
项目类别：
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

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.

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，但其潜在机制是。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聚糖。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 都会因高血糖和炎症细胞因子而全身增加。胰岛 HA 和 CD44 水平在非糖尿病受试者中可以忽略不计，但在患有 T2DM 的人类尸体供体中含量丰富。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。它们在 T2DM 中的长时间表达可能具有致病性。 4-甲基伞形酮 (4-MU) 是一种口服 HA 合成抑制剂，可清除胰岛 HA 沉积并促进这些动物的胰岛素产生。同样，CD44-/-.db/db 小鼠尽管患有糖尿病，但不会损失 β 细胞质量或患上糖尿病。此外，4-MU 治疗和 CD44 缺失对低剂量链脲佐菌素具有保护作用，这些数据共同表明了 HA 和 CD44 在肥胖中的决定性作用。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 细胞对成纤维细胞生长因子 21 的反应较弱。 FGF21 介导的 FGF 受体 1 (FGFR1) 信号传导，尤其是在 HA 存在的情况下。然而，其潜在机制及其对 T2DM β 细胞衰竭的影响尚不清楚。我们令人兴奋的初步数据表明，CD44 通过抑制 FGF21 反应来驱动 T2DM 中的 β 细胞衰竭。此外，我们建议可以重新利用已批准的药物 4-MU 来预防 T2DM 中的 β 细胞衰竭。根据这一假设，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 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 细胞质量，这些目标有可能揭示 T2DM 发展的基本新途径，并引入改善血糖的新疗法。 T2DM 的控制。