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：
8509896
负责人：
JOHN D BARKS
金额：
$ 19.44万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509896
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，急性新生儿脑损伤后，高母脂肪的摄入量是迄今为止非批准神经发育结果的危险因素。我们的初步实验和新的流行病学证据支持了这一点。现在，我们建议扩展我们的发现并研究系统性和脑髓样细胞谱系中的潜在机制。典型的美国饮食含量很高（脂肪中的卡路里的34％），饱和和N6多不饱和脂肪酸，但有限的N3脂肪酸。肥胖会在怀孕期间诱发慢性，低度炎症，并增加不良新生儿结局的风险，但尚未将孕妇体重和饮食脂肪摄入作为新生儿低氧缺血性脑损伤的危险因素。此外，新生儿脑损伤的实验模型之间的普遍限制是，动物通常被喂入低脂盘，其中14％的脂肪卡路里不反映典型的美国饮食。在初步研究中，我们比较了单侧脑缺氧 - 缺血性疾病后的结果，在饲喂低脂食物的后代与饮食中的大坝相比，脂肪中的卡路里34％。高脂饮食后代的血清和脑N3脂肪酸降低，循环单核细胞比例显着增加。在产后第7天（P7）幼崽的两个饮食组同时接受缺氧 - 缺血性病变。在高脂饮食组中，我们发现死亡率增加，恢复1或4周后的感觉运动功能较差。该提案的目的是确认这些趋势并检验假设，即脑髓样细胞表型和功能的促炎性转换是基于这些作用的机制，而高脂肪饮食则不成比例地增加了白质损伤。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特征模型中进行 7天大的大鼠的连接和暴露于8％的氧气。该模型的优势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掺入多个互补可量化功能和病理结局指标的可行性。该提案的目的是（i）在HI脑损伤的新生儿啮齿动物模型中，比较了在怀孕期间喂养低（17％）或高（34％）脂肪饮食的大坝后代的感觉运动功能和神经病理学结果。确定母体高脂对P7的低脂饮食是否会影响这些结果；（ii）确定怀孕期间的孕产妇高脂饮食是否诱导促炎性髓样细胞表型以及其后代血液和大脑的功能。这项研究将为未来的临床前和临床研究提供重要的基础，将我们的新型初步结果转化为公共卫生措施，与现代美国人群有关的人类孕产妇饮食干预措施或新生儿治疗方案。