Placental Functional Imaging to Predict Preeclampsia Therapeutic Outcomes

目前还缺乏可靠的工具来评估有希望的子痫前期治疗方法对胎盘的影响。 功能和发育；治疗效果的评估通常通过测量 母亲的平均动脉压，这并不总是与胎儿结局相关。在没有这种情况下 技术，改善对先兆子痫病理生理学的机械性理解的前景- 开发新的治疗方法以改善患者预后所必需的--很可能仍未实现。 这项工作的长期目标是开发新的功能成像方法，以改善对 先兆子痫。本申请的总体目标是建立新的功能成像方法以 纵向测量体内胎盘的血流灌注、缺血和胎盘血管生成。我们的中央 假设胎儿结局可以通过纵向监测胎盘血流、缺氧、 和使用光谱光声(Spa)和靶向对比增强超声(CEUS)的血管生成 成像。这一假设是基于我们的实验室和其他建立Spa的机构的初步数据提出的 成像作为评估体内纵向胎盘组织氧合的方法，CEUS作为评估纵向胎盘组织氧合的方法 量化体内组织灌注量和血管生成。提出这项研究的理由是改进了 子痫前期的体内纵向监测方法将提供更准确的临床前验证 先兆子痫的潜在治疗方法。在强劲的初步数据的指导下，这一假设将得到以下检验 追求两个具体目标：1)开发活体成像胎盘氧合变化的方法 对治疗的反应；以及2)开发方法来成像治疗的纵向影响 胎盘生长。在第一个目标下，将使用光谱光声成像来估计胎盘 治疗过程中的氧合作用；子痫前期的影像方法和模型 项目，降低子宫灌流压力(RUPP)大鼠，都已被证实是可行的 申请者的手。在第二个目标下，对比增强超声将在纵向上实施 先兆子痫治疗期间胎盘血流灌注的动态变化。支持这一观点的初步数据 目的探讨超声造影作为评价胎盘血流灌注和血管生成的方法。这种方法 是创新的，因为它通过转移研究重点代表了对现状的实质性偏离 从母体系统功能障碍到胎盘功能障碍，长期以来一直被认为是主要的潜在原因 调节因子在子痫前期的发展中的作用。胎盘多模式活体成像方法的建立 功能将构成对表征人的生理环境的重大改进 先兆子痫期间的胎盘；获得这一缺失的信息有望开启新的治疗方法 可供选择，并使该领域朝着改善治疗的方向迈进。这一贡献预计将具有 在预防和治疗一系列与妊娠有关的疾病方面具有广泛的翻译重要性。

There is a lack of reliable tools to assess the impact of promising treatments for preeclampsia on placental function and development; assessment of treatment efficacy is typically determined through measurements of maternal mean arterial pressure, which are not always correlated with fetal outcome. In the absence of such technology, the promise of an improved mechanistic understanding of preeclampsia pathophysiology — necessary for the development of novel treatments to improve patient outcomes — will likely remain unfulfilled. The long-term goal of this effort is to develop new functional imaging methods to improve the treatment of preeclampsia. The overall objective in this application is to establish new functional imaging methods to longitudinally measure in vivo placental perfusion, ischemia, and placental angiogenesis. Our central hypothesis is that fetal outcomes can be predicted by longitudinally monitoring placental perfusion, hypoxia, and angiogenesis using spectral photoacoustic (sPA) and targeted contrast enhanced ultrasound (CEUS) imaging. This hypothesis was formulated based on preliminary data from our lab and others establishing sPA imaging as a method to estimate longitudinal placental tissue oxygenation in vivo, and CEUS as a method to quantify in vivo tissue perfusion and angiogenesis. The rationale for the proposed research is that improved methods for longitudinal in vivo monitoring of preeclampsia will provide more accurate preclinical validation of potential treatments for preeclampsia. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) the development of methods to image in vivo placental oxygenation changes in response to therapy; and 2) the development of methods to image the longitudinal impact of therapies on placental growth. Under the first aim, spectral photoacoustic imaging will be implemented to estimate placental oxygenation during treatment; the imaging methods and the model of preeclampsia which will be used in this project, the reduced uterine perfusion pressure (RUPP) rat, have both been established as feasible in the applicants' hands. Under the second aim, contrast-enhanced ultrasound will be implemented to longitudinally track alterations in placental perfusion during preeclampsia treatment. Preliminary data in support of this objective demonstrates CEUS as a method of assessing placental perfusion and angiogenesis. This approach is innovative, because it represents a substantive departure from the status quo by shifting the research focus from maternal systemic dysfunction, to placental dysfunction, long recognized as the dominant underlying regulator in the development of preeclampsia. The establishment of multimodal in vivo imaging of placental function will constitute a significant improvement towards characterizing the physiological environment of the placenta during preeclampsia; acquiring this missing information is expected to open up new therapeutic options and move the field substantially towards improved treatment. This contribution is expected to have broad translational importance in the prevention and treatment of a range of pregnancy-associated diseases.