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.

妊娠期间胎盘功能不全会导致宫内生长受限 (IUGR)，并使后代容易患 2 型糖尿病，同时功能性 β 细胞量减少，了解子宫内 β 细胞量减少的机制对于制定预防或逆转的治疗策略至关重要。补体系统是一种对宿主防御、炎症和胎儿生存至关重要的先天免疫放大系统，但补体过度激活与妊娠并发症（包括先兆子痫）和 IUGR 降低有关。大鼠胎盘功能不全的子宫胎盘灌注压 (RUPP) 模型，在妊娠晚期 (e)14 日，流向子宫胎盘单位的血流受到机械干扰，导致胎盘缺血、母鼠高血压和 IUGR。 ，我们发表的研究表明，生长受限胎儿的 e19 胰岛中 β 细胞面积减少，细胞凋亡增加，母体补体激活增加对于高血压患者至关重要RUPP 母亲。我们的初步研究表明，RUPP 后代的 e19 胰岛中 C3 减少，巨噬细胞标记物增加。 长期目标：确定在子宫内或出生后操纵补体或巨噬细胞以减轻 IUGR 后代 β 细胞质量减少的治疗效用。 RUPP 模型中 C3、C3a 和巨噬细胞对 β 细胞质量和存活的贡献 中心假设：胎盘缺血导致 C3/C3a 和巨噬细胞减少。最终后代胰岛中巨噬细胞数量或 M1/M2 表型的变化 导致 β 细胞质量减少和细胞凋亡增加。确定胎盘缺血诱导的 β 细胞质量减少是否需要 C3 和/或 C3a 减少（目标 1）或巨噬细胞数量或表型变化（目标 2）。胎儿胰腺中发生的细胞凋亡将在出生后 15 周至 12 周内确定 C3、C3a、C3a 受体和巨噬细胞变化的时间过程。通过siRNA或在正常妊娠（子宫内或出生后）中拮抗C3aR对β细胞面积或质量的影响，将离线确定细胞凋亡和巨噬细胞，将确定通过在RUPP后代中施用C3aR激动剂来增加C3a以拯救β细胞质量的能力。评估了在子宫内或出生后使用氯膦酸盐脂质体去除胎儿巨噬细胞对有或没有的胎儿胰岛中的补体、β细胞质量和细胞凋亡的影响。这项研究具有创新性，因为它是第一个研究补体在胰腺发育中的机制作用及其对 IUGR 应激的反应，并将胰岛生物学的跨学科专业知识与补体和 RUPP IUGR 模型的专业知识结合起来。意义重大，因为它将确定在胰腺发育早期靶向补体系统或巨噬细胞是否是一种可行的治疗策略，可以在面对胎盘缺血时保留胰腺β细胞量，从而防止出现长期后果。成年期。

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