Fetal Programming of Human Newborn Energy Homeostasis Brain Networks and Infant Adiposity

本建议书描述了一项严格而全面的计划，旨在获得高级核磁共振技术方面的专家培训。 获取和分析方法、发育系统神经科学以及健康和疾病的胎儿规划 风险。拟议的研究涉及儿童肥胖症的公共健康问题，特别关注 人类新生儿能量稳态相关脑回路的特征、作用和决定因素。肥胖 是一种多因素表型。在这些因素中，能量平衡(平衡)的关键重要性，以及 调节它的下丘脑-边缘-皮质脑回路已经很好地建立起来了。然而，目前还不清楚是否 在肥胖和正常体重个体之间观察到的大脑回路的差异是一个原因或结果 肥胖症的状态。此外，对于变异的发育来源(胎儿和出生后早期)也知之甚少。 这一大脑回路及其在形成儿童肥胖倾向方面的预期作用。我的建议解决了 这一根本的知识鸿沟。我提出了一个最重要的假设，即能量平衡大脑回路a) 在出生时已经确定；b)表现出发育可塑性(胎儿编程)；以及c)在功能上 相关(预测出生后脂肪组织的增加)。K99指导阶段将在 指导胎儿健康和疾病规划(P.Wadhwa)、脑成像(P.Thompson)、 和发育系统神经科学(D.Fair)。我将首先开发新的基于核磁共振的新生儿测量方法 能量平衡背后的大脑回路，然后确定这一变化的产前决定因素 电路。专注于新生儿大脑的重要性源于这样一个逻辑，即大脑在这一点上的电路 时间还不受后天因素的影响。在R00阶段，我将招募一个新的队列，并使用重复的 措施设计，以解决该大脑回路的初始(新生)设置的功能相关性 婴儿期脂肪组织增加的背景(儿童肥胖风险的关键指标)。K99/Aim 1.开发 使用解剖、扩散和功能磁共振成像测量能量动态平衡的脑回路。因为这样 措施还没有建立在新生儿的动态平衡回路，这一目标将实现一个重要的和 然而，不仅在科学知识方面，而且在技术能力方面，都没有得到满足。K99/AIM 2.识别产前 (妊娠生物学)新生儿大脑能量平衡回路测量变异的决定因素 与婴儿肥胖症有关。R00/Aim 3.解决这些问题的生理相关性和临床意义 新的基于MRI的新生儿大脑测量通过检验测量人类新生儿能量的假设来进行 动态平衡的大脑回路可能与婴儿肥胖和随后的儿童肥胖有关 风险。R00/Aim 4.考虑婴儿出生时肥胖与预期相关的补充假设 伴随着新生儿能量平衡大脑回路的变化。意义重大。通过确定角色和决定因素 这些发现最终将为研究人类新生儿的能量稳态相关脑回路提供依据 用于随后制定旨在初级预防儿童肥胖症的战略。

This proposal describes a rigorous and comprehensive plan designed to obtain expert training in advanced MRI acquisition and analytical methods, developmental systems neuroscience, and fetal programming of health and disease risk. The proposed research relates to the public health problem of childhood obesity, with a specific focus on the characterization, role and determinants of energy homeostasis-related brain circuitry in the human newborn. Obesity is a multi-factorial phenotype. Among these factors, the critical importance of energy homeostasis (balance), and the hypothalamic-limbic-cortical brain circuitry that regulates it, is well established. However, it is unclear whether the observed difference in this brain circuitry between obese and normal-weight individuals is a cause or consequence of the obese state. Also, relatively little is known about the developmental origin (fetal and early postnatal) of variation in this brain circuitry and its prospective role in shaping propensity for childhood obesity. My proposal addresses this fundamental knowledge gap. I advance the overarching hypothesis that energy homeostasis brain circuitry a) already is established by the time of birth; b) exhibits developmental plasticity (fetal programming); and c) is functionally relevant (predicts postnatal adipose tissue accrual). The K99 mentored phase will be conducted under the mentorship of leading experts in fetal programming of health and disease (P. Wadhwa), brain imaging (P. Thompson), and developmental systems neuroscience (D. Fair). I will first develop novel MRI-based measures of the newborn brain circuitry underlying energy homeostasis, and then identify the prenatal determinants of variation in this circuitry. The importance of focusing efforts on the newborn brain derives from the logic that brain circuitry at this time is not yet influenced by postnatal factors. In the R00 phase, I will recruit a new cohort and use a repeated measures design to address the functional relevance of the initial (newborn) setting of this brain circuitry in the context of adipose tissue accrual over infancy (a key indicator of childhood obesity risk). K99/Aim 1. Develop measures of energy homeostasis brain circuitry using anatomical, diffusion and functional MRI. Because such measures have not yet been established in newborn homeostasis circuitry, this aim will fulfill an important and as yet unmet need in terms of not only scientific knowledge but also technical capability. K99/Aim 2. Identify the prenatal (gestational biology) determinants of variation in the measures of newborn brain energy homeostasis circuitry that are associated with infant adiposity. R00/Aim 3. Address the physiological relevance and clinical significance of these novel MRI-based newborn brain measures by testing the hypothesis that measures of the human newborn’s energy homeostasis brain circuitry are prospectively associated with infant adiposity and subsequent childhood obesity risk. R00/Aim 4. Consider the complimentary hypothesis that infant adiposity at birth is prospectively associated with changes in newborn energy homeostasis brain circuitry. Significance. By identifying the role and determinants of energy homeostasis-related brain circuitry in the human newborn, these findings will ultimately provide the basis for the subsequent development of strategies aimed at the primary prevention of childhood obesity.