Developmental Programming of the Liver and Kidney in Fetal Growth with or without Gene Therapy

项目总结 非传染性疾病，包括心血管疾病、高血压、中心性肥胖、2型 糖尿病和呼吸系统疾病每年造成80%的成人死亡， 负责对健康、调整后的预期寿命和生活质量产生最大影响。胎儿生长发育 节制(FGR；估计胎儿体重&lt；10%)，发生在多达10%的怀孕中， 与晚年罹患非传染性疾病的风险增加有关。这可能是因为FGR会导致 胎儿组织和器官的发育规划，以适应导致 FGR会持续到成年期，但最终会导致生理和代谢功能障碍。我们有 开发了一种以聚合物为基础的纳米颗粒的用途，这种纳米颗粒有助于将非病毒基因专门传递到 胎盘。我们的胎盘特异性纳米颗粒基因疗法能够增加人类 胰岛素样生长因子1(HIGF1)在多种动物和人胎盘模型中的表达重要的是，我们的 纳米粒子基因疗法被证明对母亲和胎儿都是安全的。我们一直以来 证明治疗可增加胎盘葡萄糖和氨基酸转运体，以及生长因子 FGR在不同模型中的表达(手术诱导、基因组操作、母体营养限制 (Mnr))，因为IGF1是大多数与胎盘相关的FGR的中心机制 功能障碍，是胎盘和胎儿生长发育的主要调节因素。本提案旨在1) 确定胎盘纳米颗粒基因治疗对胎儿发育规划的影响 在已证实的FGR豚鼠MNR模型中，妊娠晚期的肝和肾，2)确定其机制 用纳米颗粒基因疗法操纵胎盘信号会影响与胎儿肝脏的通讯 肾脏细胞在人类细胞培养模型中的作用，以及3)研究胎盘特异性的长期影响 纳米粒子基因治疗对子代肝肾生理和代谢健康的影响。初步 研究证实，胎盘特异性纳米颗粒基因治疗增加了先前存在的胎儿体重 FGR采用豚鼠MNR模型。此外，短期的胎盘特异性纳米颗粒基因治疗 使胎肝基因表达和肾脏胶原沉积与FGR相关的变化正常化，据此 建立一个模型，在该模型中可以进一步研究胎儿器官的发育规划 调查过了。这一提议具有创新性和重大意义，因为它利用了目前正在 在治疗癌症方面进行了试验，但在生殖医学的背景下，从而产生了 将为临床创新提供信息，为健康怀孕和终身健康奠定基础。

PROJECT SUMMARY Non-Communicable Diseases (NCDs), including cardiovascular disease, hypertension, central obesity, type 2 diabetes mellitus and respiratory disease, are responsible for 80% of adult deaths annually, and are responsible for having the greatest impact on health adjusted life expectancy and quality of life. Fetal growth restriction (FGR; estimated fetal weight <10th percentile), which occurs in up to 10% of pregnancies, is associated with increased risk of developing NCDs later in life. This is potentially because FGR results in developmental programming of fetal tissues and organs in order to adapt to the adverse conditions resulting in FGR, which persist into adulthood but ultimately predispose physiological and metabolic dysfunction. We have developed the use of a polymer-based, nanoparticle that facilitates non-viral gene delivery specifically to the placenta. Our placenta-specific, nanoparticle gene therapy is capable of increasing expression of human insulin-like growth factor 1 (hIGF1) in multiple animal and human placenta models. Importantly, our nanoparticle gene therapy is proven to be safe to both mother and fetus. We have consistently demonstrated that treatment increases placental glucose and amino acid transporter, and growth factor expression in diverse models of FGR (surgically-induced, genomic manipulation, maternal nutrient restriction (MNR)) because IGF1 is central to most mechanisms responsible for FGR associated with placental dysfunction, and a major regulator of placental and fetal growth and development. This proposal aims to 1) determine the impact of placental nanoparticle gene therapy treatment on developmental programming in fetal liver and kidney in late pregnancy, in the proven guinea pig MNR model of FGR, 2) Identify the mechanisms by which manipulating placenta signaling with nanoparticle gene therapy affect communication with fetal liver and kidney cells in human cell culture models, and 3) investigate the long-term impact of placenta-specific nanoparticle gene therapy on offspring liver and kidney physiology and metabolic health. Preliminary investigations confirm that placenta-specific, nanoparticle gene therapy increased fetal weight in preexisting FGR using the guinea pig MNR model. Furthermore, short-term placenta-specific nanoparticle gene therapy normalizes changes associated with FGR in fetal liver gene expression and kidney collagen deposition, hereby establishing a model in which further investigations into developmental programming of fetal organs can be investigated. This proposal is innovative and significant as it utilizes a nanoparticle technology currently being trialed in the treatment of cancer, but in the setting of reproductive medicine, thus generating knowledge that will inform clinical innovation in order to set the foundation for a healthy pregnancy and lifelong wellness.