Insulin-like Growth Factor 1 Gene Therapy; Correction of Placental Insufficiency

胰岛素样生长因子1基因治疗；

• 批准号: 8786913
• 负责人: HELEN N JONES
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786913
• 关键词: Adult; Amino Acid Transporter; Animal Model; Award; Basic Science; Biological Availability; Biology; Cardiovascular Diseases; Cells; Data; Development; Diabetes Mellitus; Diet; Disease; Fetal Growth; Fetal Growth Retardation; Fostering; Gene Transfer; Goals; Growth; Growth and Development function; Health; Hypertension; In Vitro; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Knowledge; Laboratories; Lead; Mediating; Mentors; Methods; Mission; Modeling; Molecular; Nutrient; Obesity; Outcome; Pathology; Phase; Placenta; Placental Insufficiency; Placentation; Positioning Attribute; Pregnancy; Proteins; Public Health; Recovery; Research; Research Personnel; Research Training; Risk; Site; System; Techniques; Testing; Therapeutic Intervention; Time; Training; Work; base; effective therapy; fetal; fetal programming; gene therapy; high risk; improved; in vitro Model; in vivo; infant morbidity/mortality; innovation; insight; interest; mouse model; new technology; postnatal; prevent; programs; success; treatment strategy; trophoblast; vector

Project Summary Intra-Uterine Growth Restriction (IUGR) complicates 5-10% of all pregnancies in the U.S.A and currently has no treatment. The majority of these cases are due to placental insufficiency and studies indicate that these babies are at high risk of developing obesity, diabetes and cardiovascular disease in adulthood. The long-term goal is to establish an independent laboratory with research interests in placental function and programming following placental gene transfer in order to establish potential treatment strategies for fetal growth restriction. The overall objective of this application is to develop vectors for placental Insulin-like Growth Factor 1 gene transfer in a mouse model of growth restriction and gain new insight into the placental mechanisms of IGF-1. My central hypothesis is that increased placental nutrient transport induced by over-expression of IGF-1 following IGF-1 gene therapy constitutes one mechanism responsible for the correction of fetal growth restriction by gene therapy. The hypothesis has been formulated on the basis of preliminary data produced in the applicants and mentors laboratory. The rationale behind this proposal is that it is expected to broaden the knowledge of IGF-1 actions in the placenta in vivo and yield new technologies for placental gene transfer while, at the same time, it provides the means of establishing the Candidate as an independent researcher. To test the central hypothesis and accomplish the objective of this application the candidate intends to pursue the following specific aims: 1) To demonstrate that intraplacental gene transfer of IGF-1 corrects placental insufficiency and restores placental, fetal and postnatal growth in a mouse model of IUGR (to be accomplished during the mentored phase) and 2) To determine if the correction of fetal growth restriction following IGF-1 gene transfer is due to increased placental nutrient transport (to be accomplished during the independent phase). Under the first aim the candidate will receive training in gene therapy techniques and develop strategies for placental IGF-1 gene transfer, after which the effect of over-expression of IGF-1 in the placenta on placental growth and development and fetal and post-natal growth will be analyzed. Under the second aim functional and molecular studies in vitro and in vivo will identify the involvement of placental nutrient transport in IGF-1 mediated fetal growth recovery and provide insight into placental IGF-1 mechanisms. The use of site- specific intraplacental gene transfer of IGF-1 is highly innovative, challenging current paradigms for the management of IUGR and may provide new insights into the placental mechanisms of IGF-1. It also provides an experimental means to test Barker's fetal programming hypothesis and to prevent adult diseases such as obesity, diabetes, hypertension and cardiovascular disease. The proposed research is significant because it has the potential to move the field forward in the development of and understanding of the mechanisms of placental gene therapy strategies and furthering our knowledge of IGF-1 function in the placenta. Ultimately such knowledge has the potential to lead to the development of the first effective treatment for IUGR.

项目摘要 在美国，宫内生长受限(IUGR)合并5%-10%的妊娠，目前 得不到治疗。这些病例中的大多数是由于胎盘功能不全，研究表明，这些 婴儿在成年后患肥胖症、糖尿病和心血管疾病的风险很高。长期的 目标是建立一个独立的实验室，对胎盘功能和编程有研究兴趣 在胎盘基因转移后，以建立潜在的治疗胎儿生长受限的策略。 本申请的总体目标是开发胎盘胰岛素样生长因子1基因的载体 转移到生长受限的小鼠模型中，并对IGF-1的胎盘机制有新的认识。 我的中心假设是IGF-1过度表达导致胎盘营养物质转运增加 IGF-1基因治疗是纠正胎儿生长发育的一种机制 通过基因治疗进行限制。这一假设是根据#年产生的初步数据提出的。 申请者和导师实验室。这项建议背后的理由是，预计它将扩大 了解IGF-1在体内胎盘中的作用并产生胎盘基因转移的新技术， 同时，它提供了将候选人确立为独立研究人员的手段。为了测试 中心假设，并实现此申请的目标候选人打算追求 具体目的如下：1)证明胎盘内IGF-1基因转移纠正胎盘 IUGR小鼠模型的功能不全并恢复胎盘、胎儿和出生后的生长(有待完成 在指导阶段)和2)确定IGF-1治疗后胎儿生长受限的纠正 基因转移是由于胎盘营养物质转运增加(在独立的 阶段)。在第一个目标下，候选人将接受基因治疗技术的培训，并开发 胎盘组织中IGF-1基因转移的策略及其对胎盘中IGF-1过度表达的影响 对胎盘的生长发育以及胎儿和出生后的生长发育进行分析。在第二个目标下 体外和体内的功能和分子研究将确定胎盘营养物质转运的参与 在IGF-1介导的胎儿生长恢复中，并提供对胎盘IGF-1机制的洞察。使用场地- IGF-1胎盘内特异性基因转移是一种高度创新的方法，对目前的 对IUGR的治疗，可能为IGF-1的胎盘机制提供新的见解。它还提供了 一种验证巴克的胎儿程序化假说和预防成人疾病的实验方法，如 肥胖、糖尿病、高血压和心血管疾病。这项拟议的研究意义重大，因为它 有潜力推动这一领域在发展和理解的机制 胎盘基因治疗策略和进一步了解IGF-1在胎盘中的作用。最终 这些知识有可能导致开发出第一种有效的治疗IUGR的方法。