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.

妊娠期胎盘功能不全导致宫内生长受限（IUGR），后代易患2型糖尿病，伴有功能性β细胞质量减少。了解子宫内β细胞质量减少的机制对于制定预防或逆转这种情况的治疗策略至关重要。补体系统是一种先天免疫扩增系统，对宿主防御、炎症和胎儿存活至关重要，但过度的补体激活与妊娠并发症有关，包括IUGR的先兆子痫。在大鼠胎盘功能不全的子宫胎盘灌注压降低（RUPP）模型中，在胚胎日(e)14，妊娠晚期开始时，子宫胎盘单元的血流被机械中断，导致胎盘缺血、妊娠期高血压和IUGR。利用该模型，我们发表的研究表明，生长受限胎儿e19胰岛β细胞面积明显减少，凋亡明显增加，母体补体激活增加是RUPP坝高血压的关键。我们的初步研究表明，RUPP子代e19胰岛C3降低，巨噬细胞标志物升高。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。目的：探讨巨噬细胞C3、C3a及巨噬细胞对RUPP模型β细胞质量及存活的影响。中心假说：胎盘缺血最终导致子代胰岛中C3/C3a降低，巨噬细胞数量或M1/M2表型改变

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