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: 10436997
• 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/10436997
• 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; 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（T2 D）负担不成比例地落在少数民族和经济困难的人身上 阿巴拉契亚社区。这些人口的低出生体重率也很高，这本身就是一个问题。 T2 D的独立风险因素。LBW的一个主要原因是子宫胎盘功能不全， 宫内生长受限（IUGR）。我们在妊娠晚期的妊娠大鼠中建立了子宫胎盘功能不全的模型， 结扎子宫动脉生长受限的后代显示葡萄糖刺激的胰岛素减少 减少胰岛毛细血管密度，并降低β细胞增殖。我们最近测序了 IUGR胰岛转录组在2周龄时，显示增加的表达Hyglonan合成酶2（Has 2）， 其制造细胞外基质糖胺聚糖透明质酸（HA）和主要HA受体Cd 44。 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，其酶促或氧化片段化为LMW-HA是活化性的。先前 研究表明，T2 D患者血清和脂肪组织中HA增加，HA水平或CD 44 活动提高胰岛素敏感性。尽管有证据表明，HA和HLA-HA在2型糖尿病中的作用，但研究尚未量化T2 D中的胰岛HA。 HA结合蛋白是正常的胰岛组分，并且HA水平在T2 D中改变。确定HA是否 有助于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 交互.关于HA对β细胞功能的影响的研究很少。然而，HA调节 肌动蛋白细胞骨架动力学通过调节单体G蛋白在各种细胞类型，如果发生 在β细胞中，可以对GSIS产生深远的影响。综上所述，我假设HA的丰度和大小 分布在IUGR胰岛中改变，HA大小特异性地调节体外GSIS。的目标 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HA的含量。特异性目标2的目标是确定HA是否通过以下方式在体外特异性改变GSIS： 调节单体G蛋白和相关肌动蛋白动力学。在向介入性的转变中， 方法，我们将检查是否HA含量的药理学调制正常化GSIS在IUGR胰岛 离体。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- 在T2 D中与HA相关，并提供了HA负面影响β细胞功能的有力证据。这些数据将 为我未来的R 01研究经费申请提供理由并证明其可行性 对于IUGR介导的T2 D中的HA。