Innate Immune Complement System and Developmental Programming of Functional β Cell Mass

先天免疫补体系统和功能性β细胞群的发育编程

• 批准号: 10194574
• 负责人: Emilyn Alejandro
• 金额: $ 19.36万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194574
• 关键词: Address; Adult; Adult Children; Affect; Agonist; Animals; Apoptosis; Area; Arteries; Autophagocytosis; B-Cell Development; Beta Cell; Biology; Birth; Blood flow; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Complement; Complement 3a; Complement Activation; Data; Development; Dichloromethylene Diphosphonate; Disease; Embryo; Fetal Development; Fetal Growth Retardation; Fetus; Functional disorder; Goals; Growth; Host Defense; Human; Hyperglycemia; Hypertension; IL4 gene; Immune; Individual; Inflammation; Innate Immune System; Intraperitoneal Injections; Ischemia; Knowledge; Life; Ligation; Link; Liposomes; Longevity; Lymphocyte; Malnutrition; Mechanics; Mission; Modeling; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathologic; Perfusion; Phenotype; Placental Insufficiency; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteins; Public Health; Publishing; Rattus; Regulation; Research; Risk; Risk Factors; Role; Small Interfering RNA; Small for Gestational Age Infant; Stress; Structure of beta Cell of islet; System; Therapeutic; Third Pregnancy Trimester; Time; United States National Institutes of Health; Up-Regulation; Uterus; activation product; complement C3 precursor; complement system; cytokine; diabetic; extracellular; fetal; in utero; innovation; islet; macrophage; novel therapeutic intervention; offspring; pancreas development; postnatal; preservation; pressure; prevent; programmed cell death protein 1; receptor; response; single-cell RNA sequencing; treatment strategy

Placental insufficiency during pregnancy causes intrauterine growth restriction (IUGR) and predisposes offspring to Type 2 diabetes with reductions in functional β-cell mass. Understanding the mechanism of this decrease in β-cell mass in utero is essential to developing treatment strategies to prevent or reverse it. The complement system is an innate immune amplification system essential for host defense, inflammation and fetal survival, but excessive complement activation is associated with pregnancy complications including preeclampsia with IUGR. In the reduced uteroplacental perfusion pressure (RUPP) model of placental insufficiency in rat, blood flow to uteroplacental unit is mechanically disrupted at embryonic day (e)14, beginning of third trimester, resulting in placental ischemia, high blood pressure in dam and IUGR. Using this model, our published studies demonstrated β cell area is reduced and increased apoptosis evident in e19 islet of growth restricted fetus, and increased maternal complement activation is critical for hypertension in RUPP dam. Our preliminary studies demonstrate decreased C3 and increased macrophage marker in e19 islets of RUPP offspring. Long-term goal: Determine therapeutic utility of manipulating complement or macrophages in utero or postnatally to mitigate reduced β cell mass in IUGR offspring. Objective: Assess contribution of C3, C3a and macrophages to β cell mass and survival in RUPP model. Central hypothesis: Placental ischemia results in decreased C3/C3a and change in macrophage numbers or M1/M2 phenotype in islets of offspring, ultimately leading to reduced β cell mass and increased apoptosis. Aim 1: Determine whether decrease in C3 and/or C3a (Aim 1) or change in macrophage numbers or phenotype (Aim 2) are required for placental ischemia-induced reduction in β cell mass and apoptosis in developing fetal pancreas. Time course of changes in C3, C3a, C3a receptor, and macrophages will be determined from e15 to 12 wk postnatal. Effect of decreasing C3 by siRNA or antagonizing C3aR in normal pregnancy (in utero or postnatally) on β cell area or mass, apoptosis and macrophages will be determined. Conversely, ability of increasing C3a by administration of a C3aR agonist in RUPP offspring to rescue β cell mass will be evaluated. The effect of fetal macrophage depletion using clodronate liposomes in utero or postnatally on complement, β cell mass and apoptosis in fetal islets with and without placental ischemia will be assessed. This research is innovative because it is the first to examine the mechanistic role of complement in pancreatic development and its response to IUGR stress, and combines intradisciplinary expertise in islet biology with expertise in complement and RUPP IUGR model. This contribution will be significant because it will determine if targeting complement system or macrophages early in pancreatic development is a feasible therapeutic strategy for preserving pancreatic β cell mass in the face of placental ischemia and thus preventing long term consequences in adulthood.

怀孕期间的胎盘不足会导致内在的生长限制（IUGR），并使后代对2型糖尿病产生降低的β细胞质量。了解子宫内β细胞质量减少的机制对于制定预防或逆转治疗的策略至关重要。完成系统是一种天生的免疫扩增系统，对于宿主防御，感染和胎儿存活至关重要，但是过量的完成激活与妊娠并发症有关，包括与IUGR的前美术有关。在降低大鼠的占位不足的子宫灌注压力（RUPP）模型中，在胚胎日（E）14（E）14（E）14开始时，血液流向子宫牙科单位，导致占地去，导致下端缺血，大坝和IUGR的高血压。使用该模型，我们发表的研究表明，β细胞面积减少，并增加了E19 E19生长限制胎儿胰岛的凋亡证据，而增加的母体完成激活对于Rupp DAM中的高血压至关重要。我们的初步研究表明，在Rupp后代E19胰岛中，C3降低并增加了巨噬细胞标记。长期目标：确定子宫内或巨噬细胞的治疗效用或产后的巨噬细胞减轻IUGR后代的β细胞量减少。目的：评估C3，C3A和巨噬细胞对RUPP模型中β细胞质量的贡献。中央假设：胎盘缺血会改善C3/C3A和巨噬细胞数量的变化或后代胰岛中M1/M2表型，最终最终 导致β细胞质量降低并增加凋亡。 AIM 1：确定C3和/或C3A（AIM 1）的减少或巨噬细胞数量或表型的变化（AIM 2）是置换缺血诱导的β细胞质量减少和发育中的胎儿胰腺凋亡所必需的。 C3，C3A，C3A受体和巨噬细胞的变化的时间过程将从E15到12周后确定。将确定将确定siRNA或在正常妊娠中（子宫内或产后）对C3降低C3对β细胞区域或质量，凋亡和巨噬细胞的影响。相反，将评估通过在Rupp后代施用C3AR激动剂来挽救β细胞量的C3A的能力。胎儿巨噬细胞在子宫内或产后使用氯膦酸盐脂质体对完成的影响，β细胞质量和胎儿胰岛中的β细胞质量和凋亡将评估有或没有占地去的缺血。研究之所以创新，是因为它是第一个研究完成在胰腺发展中的机理作用及其对IUGR压力的反应，并将胰岛生物学领域的学科专业知识与完成和RUPP IUGR模型相结合。这项贡献将是重要的，因为它将确定胰腺发育早期的靶向完成系统或巨噬细胞是在面对占地性缺血的情况下保存胰腺β细胞量的可行治疗策略，从而阻止了长期的后果。

项目成果

Critical Role for Macrophages in the Developmental Programming of Pancreatic β-Cell Area in Offspring of Hypertensive Pregnancies.

巨噬细胞在妊娠高血压后代胰腺β细胞区域发育编程中的关键作用。

• DOI: 10.2337/db22-0404
• 发表时间: 2022
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Root,KateM;Akhaphong,Brian;Cedars,MelissaA;Molin,AlexaM;Huchthausen,MargarettaE;Laule,ConnorF;Regal,RonaldR;Alejandro,EmilynU;Regal,JeanF
• 通讯作者: Regal,JeanF