Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

透明质酸作为 2 型糖尿病宫内生长受限诱导的胰岛功能障碍的介质

• 批准号: 10303293
• 负责人: Cetewayo Saif Rashid
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-23 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303293
• 关键词: Accounting; Actins; Address; Adipose tissue; Adult; Affect; Age; Age-Months; American; Animal Model; Appalachian Region; Applications Grants; Arteries; Attenuated; B Cell Proliferation; Beta Cell; Binding; Blood capillaries; CD44 Antigens; CD44 gene; Cell Culture Techniques; Cell physiology; Cells; Clinical Research; Communities; Cytoskeleton; Data; Distress; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Etiology; Extracellular Matrix; F-Actin; Family; Fetal Growth Retardation; Fetus; Flow Cytometry; Functional disorder; Future; GTP-Binding Proteins; Genes; Glucose; Glycosaminoglycans; Goals; Growth; HAS2 gene; HMMR gene; Human; Hyaluronan; Hyaluronidase; Immunohistochemistry; Impairment; In Vitro; Incidence; Individual; Inflammation; Insulin; Insulin Resistance; Intervention; Islet Cell; Knowledge; Leukocytes; Low Birth Weight Infant; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Weight; Monomeric GTP-Binding Proteins; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; PTPRC gene; Peripheral; Pharmacology; Population; Potassium; Prediabetes syndrome; Pregnancy; Primary Cell Cultures; Rattus; Regulation; Reporting; Research; Rest; Risk; Risk Factors; Role; Serum; Signal Pathway; Testing; Tissues; Uterus; Vulnerable Populations; angiogenesis; cell type; density; epidemiology study; ethnic minority population; gel electrophoresis; human tissue; improved; insulin secretion; insulin sensitivity; islet; offspring; pregnant; protein activation; response; rho; transcriptome

PROJECT SUMMARY Type 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressed Appalachian communities. These populations also have high rates of low birth weight (LBW), which itself is an independent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequent intrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats by ligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulin secretion (GSIS), reduced islet capillary density, and decreased β-cell proliferation. We recently sequenced the IUGR islet transcriptome at 2 weeks of age, revealing increased expression of Hyaluronan Synthase 2 (Has2), which makes the extracellular matrix glycosaminoglycan hyaluronan (HA), and Cd44, the principal HA receptor. HA has size-dependent opposing effects on angiogenesis and inflammation, with native high molecular weight (HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previous studies show increased HA in serum and adipose tissue of humans with T2D, and attenuating HA levels or CD44 activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA and HA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HA contributes to IUGR-mediated islet dysfunction, we will determine HA abundance, size, and cell type-specific interactions. There is a paucity of research regarding effects of HA on β-cell function. However, HA modulates actin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types, which if occurring in β-cells, can have profound effects on GSIS. Taken together, I hypothesize that HA abundance and size distribution are altered in IUGR islets, and HA size-specifically modulates GSIS in vitro. The goal of Specific Aim 1 is to determine whether IUGR alters abundance, size distribution and cell type-specific binding of HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro via modulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventional approach, we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR islets ex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet- associated HA in T2D and provide strong evidence that HA negatively impacts β-cell function. These data will provide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological role for HA in IUGR-mediated T2D.

项目概要 2 型糖尿病 (T2D) 的负担不成比例地由少数族裔和经济困难的人承担 阿巴拉契亚社区。这些人群的低出生体重 (LBW) 比例也很高，这本身就是一个问题 T2D 的独立危险因素。低出生体重的主要原因之一是子宫胎盘功能不全和随后的 宫内生长受限（IUGR）。我们通过以下方法建立妊娠晚期妊娠大鼠子宫胎盘功能不全的模型 结扎子宫动脉。生长受限的后代表现出葡萄糖刺激的胰岛素减少 分泌（GSIS），减少胰岛毛细血管密度，并减少β细胞增殖。我们最近对 2 周龄时的 IUGR 胰岛转录组显示透明质酸合酶 2 (Has2) 表达增加， 它使细胞外基质糖胺聚糖透明质酸 (HA) 和主要 HA 受体 Cd44 产生。 HA 对血管生成和炎症具有大小依赖性的相反作用，具有天然的高分子量 (HMW) HA 是抑制性的，其酶解或氧化裂解为 LMW-HA 是激活性的。以前的 研究表明，患有 T2D 的人血清和脂肪组织中的 HA 增加，HA 水平或 CD44 降低 活性可提高胰岛素敏感性。研究尚未量化 T2D 中的胰岛 HA，尽管有证据表明 HA 和 HA 结合蛋白是正常的胰岛成分，HA 水平在 T2D 中发生改变。判断是否HA 导致 IUGR 介导的胰岛功能障碍，我们将确定 HA 丰度、大小和细胞类型特异性 互动。关于 HA 对 β 细胞功能影响的研究很少。然而，HA 调节 通过调节多种细胞类型中的单体 G 蛋白来调节肌动蛋白细胞骨架动力学，如果发生这种情况 在 β 细胞中，可以对 GSIS 产生深远的影响。综上所述，我假设 HA 丰度和大小 IUGR 胰岛中的分布发生改变，并且 HA 在体外特异性调节 GSIS 大小。目标是 具体目标 1 是确定 IUGR 是否改变丰度、大小分布和细胞类型特异性结合 胰岛中的HA。具体目标 2 的目标是通过体外确定 HA 大小是否特异性改变 GSIS 单体 G 蛋白和相关肌动蛋白动力学的调节。在走向干预的过程中 方法，我们将检查 HA 含量的药理学调节是否使 IUGR 胰岛中的 GSIS 正常化 离体。成功完成拟议的研究将填补有关胰岛变化的关键知识空白 相关的 HA 在 T2D 中并提供了强有力的证据表明 HA 对 β 细胞功能有负面影响。这些数据将 为我未来研究病因学作用的 R01 拨款申请提供理由并证明可行性 用于 IUGR 介导的 T2D 中的 HA。