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

有或没有基因治疗的胎儿生长中肝脏和肾脏的发育规划

基本信息

批准号：
10663585
负责人：
Rebecca L Wilson
金额：
$ 8.99万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663585
关键词：
Adolescence Adult Affect Amino Acid Transporter Angiotensins Animals Area Cardiovascular Diseases Cavia Cell Culture Techniques Cells Central obesity Cessation of life Clinical Coculture Techniques Collagen Communication Data Deposition Development Diabetes Mellitus Diagnostic Procedure Disease Endocrine Female Fetal Development Fetal Growth Fetal Growth Retardation Fetal Kidney Fetal Liver Fetal Tissues Fetal Weight Fetus Fibrosis Foundations Functional disorder Gene Expression Gene Expression Profiling Genomics Glucose Growth Factor Health Hepatocyte Human Human Cell Line Hypertension Hypoxia IGF1 gene Inflammation Insulin-Like Growth Factor I Intervention Investigation Kidney Knowledge Late pregnancy Life Life Cycle Stages Liver Liver Dysfunction Metabolic Metabolic Diseases Metabolic Pathway Metabolic dysfunction Mitochondria Modeling Mothers Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Organ Pathway interactions Perinatal Physiological Physiology Placenta Polymers Pregnancy Quality of life Quality-Adjusted Life Years Renin Reproductive Medicine Research Respiratory Disease Risk Series Signal Pathway Signal Transduction Technology Testing Therapeutic Intervention Third Pregnancy Trimester Tissues Toxic effect blood pressure regulation cancer therapy clinical diagnostics drug metabolism emerging adult experimental study fetal fetal blood fetal programming gene therapy healthy pregnancy improved in utero innovation kidney cell kidney dysfunction liquid chromatography mass spectrometry male maternal nutrient restriction metabolomics nanoparticle non-viral gene delivery offspring postnatal prevent protein expression transcriptome transcriptome sequencing trophoblast uptake

项目摘要

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.

项目概要非传染性疾病 (NCD)，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，并且负责对健康调整预期寿命和生活质量产生最大影响。胎儿生长限制（FGR；估计胎儿体重<第 10 个百分位），发生在高达 10% 的妊娠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 导致胎儿组织和器官的发育规划，以适应导致的不利条件 FGR，持续到成年期，但最终导致生理和代谢功能障碍。我们有开发了一种基于聚合物的纳米颗粒，可促进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胎盘的表达多种动物和人类胎盘模型中的胰岛素样生长因子 1 (hIGF1)。重要的是，我们的纳米颗粒基因疗法已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以增加胎盘葡萄糖和氨基酸转运蛋白以及生长因子在多种 FGR 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 是负责与胎盘相关的 FGR 的大多数机制的核心功能障碍，胎盘和胎儿生长发育的主要调节者。该提案旨在 1) 确定胎盘纳米颗粒基因治疗对胎儿发育编程的影响妊娠晚期的肝脏和肾脏，在经过验证的 FGR 豚鼠 MNR 模型中，2) 通过以下方式确定机制：通过纳米颗粒基因疗法操纵胎盘信号传导，影响与胎儿肝脏的通讯人类细胞培养模型中的肾细胞，3) 研究胎盘特异性的长期影响纳米颗粒基因治疗对后代肝脏和肾脏生理和代谢健康的影响。初步的研究证实，胎盘特异性纳米颗粒基因疗法可增加已有胎儿的胎儿体重 FGR 使用豚鼠 MNR 模型。此外，短期胎盘特异性纳米颗粒基因治疗使胎儿肝脏基因表达和肾脏胶原沉积中与 FGR 相关的变化正常化，特此建立一个模型，可以进一步研究胎儿器官的发育规划调查了。该提案具有创新性且意义重大，因为它利用了目前正在开发的纳米颗粒技术。在癌症治疗中进行试验，但在生殖医学领域进行了试验，从而产生了以下知识：将为临床创新提供信息，以便为健康怀孕和终身健康奠定基础。