Advancing Methods for Safe, Noninvasive, Real Time Assessment of Placenta Development and Function Across Pregnancy (R21 Clinical Trial Not Allowed)

Funding Opportunity Description Background The Human Placenta Project (HPP) is an initiative aimed at revolutionizing our understanding of the human placenta. By accelerating the development and application of innovative technologies, development of novel biomarkers which reflect placental status, and application of in-depth analysis of existing data and sample collections, researchers will be able to produce a new dynamic picture of placental structure and function in real time, one that assesses key developmental trajectories of placental formation and functional cues that are critical for successful human pregnancy. It is expected that the insights resulting from these approaches will ultimately lead to new ways to treat, cure, and even prevent placental dysfunction disorders such as preeclampsia, fetal growth restriction, spontaneous preterm birth, and stillbirth. Given the requirements for these approaches, it is likely that the methods developed will also be applicable to assessment of other internal organs, thus the impact may be far reaching. There remains an urgent need for effective methods that allow safe real-time assessment of placenta development and function across gestation. The NICHD launched the HPP in 2014 to address this critical gap. NICHD has made nearly 40 awards and invested over $87M. There has been progress across multiple fronts, including MRI, Ultrasound, other novel imaging methods, extracellular vesicle analysis, and an array of omics approaches. However, making the jump from potential new approaches to clinical implementation requires additional clinical studies to provide confirmation and validation. In addition, by necessity the individual HPP awards represented primarily a single approach, and development of integrated approaches may provide the greatest clinical potential. It is noted that the HPP has stimulated research globally and there have been advances in centers around the world. This initiative would be open to all investigators, foreign or domestic. This Funding Opportunity Announcement (FOA) invites grant applications that seek to advance or clinically validate emerging novel approaches for the development of safe, real-time, non-invasive (or minimally invasive) methods to assess the development and function of the human placenta across pregnancy This will facilitate the development of valuable clinical and research tools to enhance our understanding of placental biology and improve our clinical management of pregnancy. Scope of Research to be Performed This FOA is for the advancement of novel methods for assessing the placenta’s real time in vivo status with the ultimate goal of human use across pregnancy. Special consideration will be given to applications that develop methods that are applicable throughout pregnancy, preferably starting in early gestation during the period of trophoblast invasion and remodeling of the uterine spiral arteries, and which facilitate assignment of relative risk for pregancy complications. The placenta is a dynamic organ which changes over the course of pregnancy. To be helpful, assessments need to yield results within a time frame that reflects the current structural/functional status. However, real-time is not meant to imply instantaneous results. For this R21 mechanism, there is strong interest in novel high risk/high reward approaches. Specific Requirements All proposed research teams should include at least one obstetric clinician to provide insights into current or potential clinical functional or safety limitations of the chosen technology. They should have sufficient involvement to ensure that the proposed technology would be feasible in a clinical setting. It is strongly recommended that a biostatistician is included on any applications that propose clinical studies. The range of additional disciplines included may be either broad or relatively narrow (e.g., various subspecialties within a given field) as appropriate to the scientific goals of the application. The application should reflect the expertise of the proposed team. Strong academic-industrial partnerships are welcomed. The rapid advancement of research in this area through data sharing is a priority for the HPP. Applicants are encouraged to share their data in real time to magnify the potential impact of their work through dissemination to the scientific community. NIH data sharing guidance is provided at this link: http://grants.nih.gov/policy/sharing.htm General Technology Characteristics This FOA promotes the advancement and/or further clinical validation of tools and technologies to enable real-time measurement of human placental processes that are currently relatively inaccessible during pregnancy and to assess changes in these processes as development progresses, including but not limited to: Anatomic and structural changes of the placenta across development. Villous cell structure and function. Blood flow, oxygenation, diffusion, and perfusion within the placenta. Maternal-fetal nutrient transfer across the placenta. Metabolic changes within the placenta including, but not limited to, oxygenation, oxidative stress, choline, lipids and lactate, and including measures of placental proteins and gene expression. Placental barrier (targeted, regional) permeability and function in the human placenta. Regulation of maternal and fetal immunologic function involved in placental processes. Circulating factors or other biomarkers that reflect placental status There is high interest in applications focused on the development of biosensors and devices capable of multiplex analysis of molecules that reflect placental status from small samples of non-blood sources including saliva, breath, urine, or vaginal secretions. This FOA encourages the use of multi-modal approaches to develop signatures of placenta status that allow for potential risk stratification in the clinical setting, including application of novel machine learning approaches or data analytics to development of risk assessment indices. Solutions describing existing, well-established and/or currently supported approaches, especially commonly used strategies, are not of interest unless a compelling case is made that significant, quantifiable advance are proposed, and/or the methods and measures are used in unique combinations not previously tested together for the real-time assessment of human placental structure, development, and function. This FOA is primarily intended to move nascent novel technologies forward. Applications that propose novel combinations of approaches are welcomed. Applications that propose completely new technologies for placenta assessment must provide a strong scientific premise and supportive preliminary data. Applicants are encouraged to contact Program Staff if they are uncertain about the suitability of their proposed studies. For novel technologies proposed for measurement of circulating factors, any placental molecules utilized do not need to be predictive of abnormal placental function, but there should at least be potential for adding novel predictive biomarkers. Applications proposing discovery of biomarkers as a byproduct of technology development and testing are allowed. However, applications whose primary focus is on biomarker discovery will be given low priority. Investigators interested in focusing on placental biomarker discovery should consider other funding opportunities. Projects that are considered low priority for this FOA include: Development of technologies that can only be applied in the third trimester of pregnancy or postpartum. Projects that only focus on data collection, data processing, data analysis, and computational modeling and simulation without direct application to placenta assessment or development of placenta risk indices. Basic research and studies of disease mechanisms that are not part of technology advancement or validation. Projects directed at understanding placental biology without the advancement or validation of novel technology to assess placental structure or function in real-time. Development of technology that has little potential for utility in late first trimester-early second trimester unless the conditions listed below are met. Development of projects whose primary focus is on the collection and analysis of imaging or omics data for biomarker identification or validation. Development of methods for isolation of placental vesicles or other circulating factors unless done in association with transformative assessment or implementation approaches with high clinical potential. Development of methodologies or technologies that are contraindicated for use in human pregnancy. Projects in non-mammalian systems that have little potential to be applied to human placenta assessment. This funding opportunity is to facilitate advancement and validation of novel technology that may be used across pregnancy for assessment of placental structure and/or function. Achievement of this goal may require the use of multiple approaches and some may not be able to be utilized within the first trimester at this time. Projects which are directed at development of technologies with little potential for use in the first trimester will be accepted, provided: The reason(s) it cannot be used in the first trimester is detailed. The potential for use in the first trimester is addressed. The value of the technology to the goals of the Human Placenta Project is justified. It is recognized that advancement of these novel technologies may require use of animal models. Studies carried out exclusively in animals may be proposed; however, the pathway for translation into humans and potential safety and technical issues associated with human application of the technology/tools must be clear.