Fetal Programming of Human Newborn Energy Homeostasis Brain Networks

人类新生儿能量稳态大脑网络的胎儿编程

基本信息

批准号：
10758984
负责人：
Jerod Michael Rasmussen
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758984
关键词：
Address Adipose tissue Age Anatomy Back Biological Markers Biology Birth Body mass index Brain Brain imaging Breathing Cerebrum Chemical Shift Imaging Cholesterol Data 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 Health High Density Lipoproteins Homeostasis Human Hydrocortisone Hypothalamic structure Immune Immune system Individual Individual Differences Infant Inflammatory Insulin Interleukin-6 Intervention Knowledge Life 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 Surface System TNF gene Technology Term Birth Testing Time Training Triglycerides Validation Variant Weight analytical method brain circuitry brain magnetic resonance imaging 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 newborn adiposity 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.

该提案描述了旨在获得高级 MRI 专家培训的严格而全面的计划采集和分析方法、发育系统神经科学以及胎儿健康和疾病编程拟议的研究涉及儿童肥胖的公共卫生问题，特别关注儿童肥胖的风险。人类新生儿能量稳态相关脑回路的特征、作用和决定因素。是一个多因素表型，在这些因素中，能量稳态（平衡）至关重要。调节它的下丘脑-边缘-皮质大脑回路已被充分确定，但尚不清楚是否存在这种情况。观察到肥胖者和正常体重者大脑回路的差异是原因还是结果此外，对于变异的发育起源（胎儿和产后早期）知之甚少。我的建议涉及这种大脑回路及其在塑造儿童肥胖倾向中的预期作用。我提出了这一基本的知识差距：能量稳态大脑电路a) 出生时就已经确定；b) 表现出发育可塑性（胎儿编程）；并且 c) 具有功能性；相关（预测产后脂肪组织的增长）。K99 指导阶段将在胎儿健康和疾病规划 (P. Wadhwa)、脑成像 (P. Thompson) 领域领先专家的指导我将首先开发基于 MRI 的新生儿新测量方法。能量稳态的大脑回路，然后确定这种变化的产前决定因素将精力集中在新生儿大脑上的重要性源于大脑电路的逻辑。时间还没有受到后天因素的影响，在R00阶段，我会招募一个新的队列，并使用重复的队列。措施设计旨在解决该大脑回路的初始（新生儿）设置的功能相关性婴儿期脂肪组织累积的背景（儿童肥胖风险的关键指标）K99/目标 1. 发展。使用解剖、扩散和功能 MRI 来测量能量稳态脑回路。尽管尚未在新生儿稳态电路中建立措施，但这一目标将实现一个重要且重要的目标 K99/目标 2. 确定产前的需求尚未得到满足。（妊娠生物学）新生儿大脑能量稳态电路测量变化的决定因素与婴儿肥胖相关。R00/目标 3。解决这些问题的生理相关性和临床意义。通过测试测量人类新生儿能量的假设，基于 MRI 的新型新生儿大脑测量大脑回路稳态可能与婴儿肥胖和随后的儿童肥胖有关 R00/目标 4. 考虑婴儿出生时肥胖是前瞻性相关的补充假设。与新生儿能量稳态大脑电路的意义。人类新生儿能量稳态相关脑回路的研究，这些发现最终将提供基础以便随后制定旨在一级预防儿童肥胖的战略。