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.

项目摘要 2型糖尿病（T2D）燃烧不成比例地取决于少数民族，经济困扰 阿巴拉契亚社区。这些人群还具有很高的低出生体重（LBW），这本身就是 T2D的独立危险因素。 LBW的一个主要原因是子宫阶层不足，随后 宫内生长限制（IUGR）。我们对晚期妊娠怀孕大鼠的子宫牙科不足进行建模 连接子宫动脉。增长限制的后代显示减少了葡萄糖刺激的胰岛素 分泌（GSIS），胰岛毛细血管密度降低和改善的β细胞增殖。我们最近对 IUGR胰岛在2周龄时的转录组，揭示了透明质酸合酶2（HAS2）的表达增加（HAS2）， 这使细胞外基质糖胺聚糖透明质酸（HA）和主要HA受体CD44。 HA对血管生成和感染具有尺寸依赖性相反的影响，天然高分子量 （HMW）HA被抑制作用及其酶促或氧化碎片，以激活LMW-HA。以前的 研究表明，具有T2D的人类的血清和脂肪组织的HA增加，并衰减HA水平或CD44 活性提高了胰岛素敏感性。研究尚未量化胰岛HA在T2D目的地的证据中 HA结合蛋白是正常的胰岛成分，HA水平在T2D中发生了变化。确定HA是否是否 有助于IUGR介导的胰岛功能障碍，我们将确定HA抽象，大小和细胞类型特异性 互动。关于HA对HA对β细胞功能的影响的研究很少。但是，HA调节 通过调节多种细胞类型中单体G蛋白的调节，肌动蛋白细胞骨架动力学，如果发生的话 在β细胞中，可以对GSI产生深远的影响。综上所述，我假设HA抽象和大小 IUGR胰岛中的分布发生了变化，并且在体外特定于GSIS特定调节。目标 具体目标1是确定IUGR是否改变了抽象，大小分布和特定于细胞类型的结合 胰岛中的HA。特定目标2的目的是确定HA大小特定于在体外改变GSIS是否通过 单体G蛋白和相关肌动蛋白动力学的调节。迈向介入 方法，我们将检查HA含量的药物调制是否使IUGR胰岛中的GSI归一化 前体。成功完成拟议的研究将填补有关胰岛变化的关键知识差距 - 在T2D中相关的HA，并提供了有力的证据表明HA对β细胞功能产生负面影响。这些数据将 提供理由并证明我未来的R01赠款申请的可行性调查了病因 用于IUGR介导的T2D中的HA。