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

人类新生儿能量稳态大脑网络和婴儿肥胖的胎儿编程

基本信息

批准号：
10022151
负责人：
Jerod Michael Rasmussen
金额：
$ 10.86万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022151
关键词：
Address Adipose tissue Age Anatomy Back Biological Markers Biology Birth Brain Brain imaging Breathing Cerebrum Chemical Shift Imaging Cholesterol Data Deltastab Development Developmental Biology Diet Diffusion Magnetic Resonance Imaging Disease Drug or chemical Tissue Distribution Dual-Energy X-Ray Absorptiometry Early identification Endocrine Endocrine system Enrollment Environment Equilibrium Etiology Exhibits Fatty acid glycerol esters Functional Magnetic Resonance Imaging Funding Mechanisms Genetic Risk Gestational Age Glucose Graph Growth HDL-triglyceride Health Homeostasis Human Hydrocortisone Hypothalamic structure Immune Immune system Individual Individual Differences Infant Inflammatory Insulin Interleukin-6 Intervention Knowledge Life Link Lipids Logic Machine Learning Magnetic Resonance Imaging Maternal-fetal medicine Measures Mediating Mentors Mentorship Metabolic Methods Modeling Neurologic Neurosciences Newborn Infant Nonesterified Fatty Acids Obesity Outcome Phase Phenotype Physics Physiological Pregnancy Primary Prevention Principal Component Analysis Procedures Process Public Health Research Research Proposals Rewards Risk Risk Factors Role Satiation Scientific Advances and Accomplishments Shapes Standardization Structure Surface System TNF gene Term Birth Testing Time Training Triglycerides Validation Variant Weight analytical method base brain circuitry career career development clinically significant cohort connectome cost effective data reduction design developmental plasticity disorder risk energy balance fetal fetal programming gestational weight gain gray matter improved infancy infant adiposity metabolic rate neuroimaging novel obesity in children obesity risk obesogenic obstetrical complication population based postnatal predictive modeling prenatal prenatal stress prepregnancy programs prospective random forest recruit sex skills vector white matter

项目摘要

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.

该建议描述了一项严格而全面的计划，旨在获得高级MRI的专家培训采集和分析方法，发展系统神经科学以及健康与疾病的胎儿编程风险。拟议的研究与儿童肥胖的公共卫生问题有关，具体侧重于人类新生儿中与能量稳态相关的脑电路的表征，作用和确定。肥胖是一种多因素表型。在这些因素中，能量稳态（平衡）的重要性调节其调节的下丘脑 - 纤维 - 皮层脑回路已建立得很好。但是，目前尚不清楚是否观察到肥胖和正常体重个体之间这种脑电路的差异是原因或结果肥胖国家。同样，关于变异的发育起源（胎儿和早期）的了解相对较少在这个脑电路及其在塑造儿童对象的承诺中的前瞻性作用。我的提议解决了这个基本知识差距。我推进了能量稳态脑电路a的总体假设a）在出生时已经建立了； b）表现出发育可塑性（胎儿编程）； c）在功能上是相关（预测产后脂肪组织的负体）。 K99修正阶段将在胎儿健康与疾病胎儿编程（P. Wadhwa），脑成像（P. Thompson）的遗传专家（P. Wadhwa），和开发系统神经科学（D. Fair）。我将首先制定新生儿基于MRI的新颖措施能量体内稳态的脑电路，然后确定其变异的产前决定剂电路。将精力集中在新生大脑上的重要性来自于大脑回路的逻辑时间尚未受到产后因素的影响。在R00阶段，我将招募一个新的队列并使用重复措施设计以解决该大脑电路初始（新生）设置的功能相关性脂肪组织对婴儿期的负面影响（儿童肥胖风险的关键指标）。 K99/AIM 1。开发使用解剖学，扩散和功能性MRI的能量体内稳态脑电路的度量。因为这样尚未在新生儿体内平衡巡回赛中建立措施，这一目标将实现重要的和然而，就科学知识，技术能力而言，未满足的需求。 K99/AIM 2。识别产前（妊娠生物学）确定新生儿脑能量体内稳态电路的变化，与婴儿肥胖有关。 r00/aim 3。解决这些物理相关性和临床意义基于MRI的新型新生儿大脑测量通过测试人类新生儿能量的假设稳态脑电路前景与婴儿肥胖和随后的儿童对象相关风险。 R00/AIM 4。考虑以下假设，即婴儿出生时的肥胖可能与随着新生儿能量稳态脑电路的变化。意义。通过确定角色和决定者在人类新生儿中与能量体内稳态相关的脑电路的，这些发现最终将提供基础为了制定旨在主要预防儿童对象的战略。