Fetal Programming of Human Newborn Energy Homeostasis Brain Networks

该提案描述了一个严格而全面的计划，旨在获得先进的MRI专家培训 采集和分析方法，发育系统神经科学，以及健康和疾病的胎儿编程 风险拟议的研究涉及儿童肥胖的公共卫生问题，特别关注 人类新生儿能量稳态相关脑回路的表征、作用和决定因素。肥胖 是一种多因子表型。在这些因素中，能量稳态（平衡）的至关重要性，以及 下丘脑-边缘系统-皮质脑回路来调节它，已经很好地建立起来。然而，目前尚不清楚是否 观察到的肥胖和正常体重个体之间大脑回路的差异是原因还是结果 肥胖的国家。此外，相对较少的是知道的发展起源（胎儿和出生后早期）的变化 以及它在塑造儿童肥胖倾向中的潜在作用。我的建议是 这一基本的知识鸿沟。我提出了一个总体假设，即能量稳态大脑回路a） 在出生时已经建立; B）表现出发育可塑性（胎儿编程）;以及c）在功能上 相关（预测产后脂肪组织累积）。K99辅导阶段将在 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.公平）。我将首先开发新的基于核磁共振的新生儿测量方法， 大脑回路潜在的能量稳态，然后确定产前决定因素的变化， 电路把精力集中在新生儿大脑上的重要性来自于这样一种逻辑，即大脑回路在这个过程中 时间还不受产后因素的影响。在R 00阶段，我将招募一个新的队列， 措施设计，以解决功能的相关性的初始（新生儿）设置的这种大脑回路中， 在婴儿期脂肪组织增加的背景下（儿童肥胖风险的关键指标）。K99/Aim 1.发展 使用解剖学、弥散和功能性MRI测量能量稳态脑回路。因为这样 虽然在新生儿体内平衡回路中还没有建立措施，但这一目标将实现一个重要的， 然而，在科学知识和技术能力方面的需求都没有得到满足。K99/Aim 2.识别产前 （妊娠生物学）新生儿脑能量稳态回路测量变化的决定因素， 与婴儿肥胖症有关R 00/目标3.解决这些生理相关性和临床意义 一种新的基于MRI的新生儿大脑测量方法，通过测试人类新生儿能量测量的假设， 内稳态脑回路与婴儿肥胖和随后的儿童肥胖症的前瞻性相关性 风险R 00/目标4.考虑到婴儿出生时肥胖与婴儿出生时肥胖症 新生儿能量平衡脑回路的变化意义通过确定作用和决定因素， 在人类新生儿中与能量稳态相关的脑回路中，这些发现将最终提供基础 随后制定旨在一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.