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.

项目总结 2型糖尿病(T2D)的负担不成比例地落在少数民族和经济困难的身上 阿巴拉契亚社区。这些人群也有很高的低出生体重率(LBW)，这本身就是一个 T2D的独立危险因素。LBW的一个主要原因是子宫胎盘功能不全和随后 宫内生长受限(IUGR)。我们通过建立妊娠晚期大鼠子宫胎盘功能不全模型 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 胰岛毛细血管密度降低，β-细胞增殖减少。我们最近测序了 IUGR胰岛2周龄转录组，显示透明质酸合成酶2(Has2)表达增加， 这使细胞外基质糖胺聚糖透明质酸(HA)和CD44，主要的HA受体。 HA对血管生成和炎症具有大小依赖的相反作用，具有天然的高分子量 (HMW)HA被抑制，其对LMW-HA的酶或氧化断裂被激活。上一首 研究表明，患有T2D的人血清和脂肪组织中的HA增加，并降低HA或CD44水平 运动可以改善胰岛素敏感性。研究尚未量化胰岛HA在T2D，尽管证据表明HA和 HA结合蛋白是正常的胰岛成分，在T2D中HA水平发生变化。要确定HA是否 导致IUGR介导的胰岛功能障碍，我们将确定HA的丰度、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较少。然而，HA可以调节 肌动蛋白在多种细胞类型中通过调节单体G蛋白的细胞骨架动力学，如果发生 在β细胞中，可以对GSI产生深远的影响。综上所述，我假设HA的丰度和大小 IUGR胰岛中的分布发生改变，HA在体外对GSIS进行大小特异性调节。的目标是 具体目的1是确定IUGR是否改变了丰度、大小分布和细胞类型特异性结合 胰岛中的HA。特异性目标2的目标是确定HA大小特异性是否通过体外改变GSIS 单体G蛋白的调节及其相关的肌动蛋白动力学。在向干预性的转变中 方法，我们将检查药物调节HA含量是否使IUGR胰岛GSIS正常化 体外实验。拟议研究的成功完成将填补有关胰岛变化的关键知识空白-- 与T2D相关的HA，提供了HA对β细胞功能产生负面影响的有力证据。这些数据将 为我未来的R01拨款申请提供理由并证明其可行性，以研究病因作用 在IUGR介导的T2D中用于HA。