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

描述(由申请人提供)：在美国，宫内生长受限(IUGR)导致5%-10%的妊娠并发症，目前还没有治疗方法。这些病例中的大多数是由于胎盘功能不全造成的，研究表明，这些婴儿患上 成年后患上肥胖症、糖尿病和心血管疾病。长期目标是建立一个独立的实验室，研究胎盘基因转移后的胎盘功能和编程，以建立潜在的胎儿生长受限的治疗策略。这项应用的总体目标是在生长受限的小鼠模型中开发胎盘胰岛素样生长因子1基因转移的载体，并对IGF-1的胎盘机制有新的认识。我的中心假设是，IGF-1基因治疗后IGF-1过度表达导致的胎盘营养物质转运增加是通过基因治疗纠正胎儿生长受限的机制之一。这一假设是根据申请者和导师实验室提供的初步数据提出的。这项建议背后的理由是，它有望扩大对IGF-1在体内胎盘中作用的了解，并产生用于胎盘基因转移的新技术，同时，它提供了确立候选人作为独立研究人员的手段。为了验证中心假设并实现这一应用的目标，候选人打算追求以下特定目标：1)证明胎盘内IGF-1基因转移纠正胎盘功能不全，并在IUGR小鼠模型中恢复胎盘、胎儿和出生后的生长(将在指导阶段完成)和2)确定在IGF-1基因转移后纠正胎儿生长受限是否由于胎盘营养物质运输增加(将在独立阶段完成)。在第一个目标下，候选人将接受基因治疗技术方面的培训，并开发胎盘IGF-1基因转移的策略，然后将分析胎盘中IGF-1过表达对胎盘生长发育以及胎儿和出生后生长的影响。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在IGF-1介导的胎儿生长恢复中的参与，并为深入了解胎盘IGF-1的机制提供依据。利用IGF-1定点胎盘内基因转移是高度创新的，对目前IUGR的治疗模式提出了挑战，并可能为IGF-1的胎盘机制提供新的见解。它还提供了一种实验手段来检验巴克的胎儿编程假说，并预防肥胖、糖尿病、高血压和心血管疾病等成人疾病。这项拟议的研究具有重要意义，因为它有可能推动该领域在胎盘基因治疗策略的开发和机制的理解方面取得进展，并进一步加深我们对IGF-1在胎盘中的作用的了解。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。 公共卫生相关性：拟议的研究和培训与公共卫生相关，因为胎盘基因转移的发展和对胎盘中IGF-1功能的了解的增加将导致潜在的治疗胎盘功能不全、胎儿生长受限和降低发生糖尿病等成人疾病的风险。因此，拟议的研究与国家卫生研究院的任务有关，该部分涉及促进创新的研究战略及其应用，以此作为最终保护和改善健康的基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research and training is relevant to public health because the development of placental gene transfer and the increased understanding of IGF-1 function in the placenta would lead to a potential treatment for Placental Insufficiency, Fetal Growth Restriction and a reduced risk of developing adult diseases such as diabetes. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to fostering innovative research strategies and their applications as a basis for ultimately protectin and improving health.