Maternal Diet and Susceptibility to Neonatal Brain Injury

描述（由申请人提供）：我们的新假设是，高母亲脂肪摄入量是急性新生儿脑损伤后不良神经发育结局的一个迄今未被认识的危险因素。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脂肪酸含量有限。肥胖可诱发妊娠期慢性、低度炎症，并增加新生儿不良结局的风险，但母体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，在新生儿脑损伤的实验模型中，一个普遍的限制是，动物通常被喂食低脂肪的食物，其中14%的卡路里来自脂肪，这与典型的美国饮食不一致。在初步研究中，我们比较了单侧脑缺氧缺血后的结果，在低脂饲料和34%的卡路里来自脂肪的饮食中的坝的后代。高脂肪饮食的后代血清和脑n3脂肪酸减少，循环单核细胞比例显著增加。在出生后第7天（P7），两个饮食组的幼犬同时发生缺氧缺血性损伤。在高脂肪饮食组，我们发现死亡率增加，恢复1或4周后感觉运动功能变差。本研究的目的是证实这些趋势，并验证以下假设：脑髓细胞表型和功能的促炎转换是这些影响的潜在机制，以及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典型模型中进行

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.