Maternal Diet and Susceptibility to Neonatal Brain Injury

母亲饮食与新生儿脑损伤的易感性

基本信息

批准号：
8685297
负责人：
JOHN D BARKS
金额：
$ 22.67万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685297
关键词：
Acute Adult Adverse effects Affect Age American Animals Asphyxia Birth Blood Brain Brain Injuries Calories Caring Carotid Arteries Cell Lineage Cell physiology Cerebral Ischemia-Hypoxia Chronic Clinic Clinical Research Comorbidity Conflict (Psychology)Data Development Diabetes Mellitus Diet Dietary Fats Dietary Intervention Disease Docosahexaenoic Acids Encephalopathies Endocrine Epidemiology Experimental Models Exposure to Fat-Restricted Diet Fatty Acids Fatty acid glycerol esters Female of child bearing age Fetal Macrosomia Fetus Foundations Funding Future Goals Health Human Hypoxia Infarction Inflammation Inflammatory Injury Intake Investigation Ischemia Ischemic-Hypoxic Encephalopathy Laboratories Laboratory Rat Lactation Lesion Ligation Link Measures Mechanics Mental Depression Metabolic Michigan Middle Cerebral Artery Occlusion Modeling Mus Myeloid Cells Neonatal Neonatal Brain Injury Neuraxis Neurologic Newborn Infant Nutritional Obesity Omega-3 Fatty Acids Outcome Outcome Measure Oxygen Pathogenesis Patients Perinatal Brain Injury Peripheral Phenotype Polyunsaturated Fatty Acids Population Predisposition Pregnancy Pregnancy Outcome Public Health Publishing Rattus Recovery Reperfusion Therapy Reporting Research Risk Risk Factors Rodent Rodent Model Sensorimotor functions Serum Severities Staging Stroke Testing Therapeutic Intervention Time Translating Treatment Protocols Weight Woman cost disability feeding fetal functional disability high risk ischemic lesion lipid mediator monocyte mortality natural hypothermia neonatal hypoxic-ischemic brain injury neurodevelopment neuroinflammation neuropathology neuroprotection novel offspring postnatal pre-clinical pre-clinical research pregnant prenatal public health relevance pup research clinical testing research study trend white matter injury

项目摘要

DESCRIPTION (provided by applicant): Our novel hypothesis is that a high maternal fat intake is a heretofore un-appreciated risk factor for adverse neurodevelopmental outcome after acute neonatal brain injury. This is supported by our preliminary experiments and new epidemiologic evidence. We now propose to extend our findings and to investigate underlying mechanisms in the systemic and brain myeloid cell lineage. The typical US diet is high in fat (about 34% of calories from fat), with abundant saturated and n6 polyunsaturated fatty acids but limited n3 fatty acids. Obesity induces chronic, low-grade inflammation during pregnancy and increases risk for adverse neonatal outcomes, yet maternal weight and dietary fat intake have not been evaluated as risk factors for neonatal hypoxic-ischemic brain injury. Furthermore a pervasive limitation among experimental models of neonatal brain injury is that animals are typically fed a low-fat chow, with 14% of calories from fat that does not reflect the typical US diet. In preliminary studies we compared outcome, after unilateral cerebral hypoxia-ischemia, in progeny of dams fed low-fat chow vs. a diet with 34% of calories from fat. The high-fat diet progeny had reduced serum and brain n3 fatty acids, and a marked increase in proportion of circulating monocytes. On postnatal day 7 (P7) pups from both diet groups concurrently underwent hypoxic-ischemic lesioning. In the high fat diet group, we found increased mortality, and worse sensorimotor function after a 1 or 4-week recovery. The goal of this proposal is to confirm these trends and to test the hypotheses that a pro-inflammatory switch in brain myeloid cell phenotype and function is the mechanism that underlies these effects, and that a high fat diet disproportionately increases white matter injury. Studies will be conducted in a well-characterized model of neonatal hypoxic-ischemic brain injury elicited by unilateral carotid artery ligation and exposure to 8% oxygen in 7-day-old rats. Strengths of the model include the ability to titrate severity of injury by varying the duration of hypoxia and the feasibility of incorporatig multiple complementary quantifiable functional and pathological outcome measures. The Aims of the proposal are (i) In a neonatal rodent model of HI brain injury, to compare sensorimotor function and neuropathology outcomes in offspring of dams who are fed low (17%) or high (34%) fat diets during pregnancy and lactation. To determine if reversion of maternal high fat to low fat diet on P7 influences these outcomes; (ii) To determine if maternal high fat diet during pregnancy and lactation induces a pro- inflammatory myeloid cell phenotype and function in blood and brain of their progeny. This line of research will provide essential building blocks for future preclinical and clinical research to translate our novel preliminary results into public heath measures, human maternal dietary interventions or neonatal treatment regimens that are relevant to the modern U.S. population.

描述（由申请人提供）：我们的新假设是，母亲高脂肪摄入是急性新生儿脑损伤后神经发育不良结果的一个迄今为止未被认识到的危险因素。我们的初步实验和新的流行病学证据支持了这一点。我们现在建议扩展我们的发现并研究系统和脑髓细胞谱系的潜在机制。典型的美国饮食脂肪含量高（约 34% 的热量来自脂肪），含有丰富的饱和脂肪酸和 n6 多不饱和脂肪酸，但 n3 脂肪酸有限。肥胖会在妊娠期间诱发慢性、低度炎症，并增加新生儿不良结局的风险，但母亲体重和膳食脂肪摄入量尚未被评估为新生儿缺氧缺血性脑损伤的危险因素。此外，新生儿脑损伤实验模型中普遍存在的局限性是，动物通常喂食低脂食物，其中 14% 的卡路里来自脂肪，这并不反映典型的美国饮食。在初步研究中，我们比较了单侧大脑缺氧缺血后，喂食低脂食物的母鼠的后代与摄入 34% 卡路里来自脂肪的饮食的母鼠的结果。高脂肪饮食的后代血清和脑中 n3 脂肪酸减少，循环单核细胞比例显着增加。出生后第 7 天（P7），两个饮食组的幼崽同时经历缺氧缺血性损伤。在高脂肪饮食组中，我们发现死亡率增加，恢复 1 或 4 周后感觉运动功能更差。该提案的目的是确认这些趋势并测试以下假设：脑髓细胞表型和功能中的促炎性转变是这些影响的机制，并且高脂肪饮食不成比例地增加白质损伤。研究将在单侧颈动脉引起的新生儿缺氧缺血性脑损伤的良好表征模型中进行 7 日龄大鼠的结扎和暴露于 8% 氧气。该模型的优点包括通过改变缺氧持续时间来滴定损伤严重程度的能力以及纳入多种互补的可量化功能和病理结果测量的可行性。该提案的目的是 (i) 在 HI 脑损伤的新生儿啮齿动物模型中，比较在怀孕和哺乳期间喂养低脂肪 (17%) 或高脂肪饮食 (34%) 的母鼠后代的感觉运动功能和神经病理学结果。确定孕产妇在第 7 个月从高脂肪饮食恢复为低脂肪饮食是否会影响这些结果； (ii) 确定母亲在怀孕和哺乳期间的高脂肪饮食是否会诱导其后代的血液和大脑中促炎性骨髓细胞表型和功能。这一系列研究将为未来的临床前和临床研究提供重要的基础，将我们新颖的初步结果转化为与现代美国人口相关的公共卫生措施、人类孕产妇饮食干预或新生儿治疗方案。