Maternal Diet and Susceptibility to Neonatal Brain Injury

描述(由申请人提供)：我们的新假设是，在急性新生儿脑损伤后，母亲高脂肪摄入量是迄今为止未被认识到的不良神经发育结局的危险因素。我们的初步实验和新的流行病学证据支持了这一点。我们现在建议扩大我们的发现，并研究系统和脑髓系细胞谱系的潜在机制。典型的美国饮食是高脂肪(大约34%的卡路里来自脂肪)，含有丰富的饱和脂肪酸和n6多不饱和脂肪酸，但有限的n3脂肪酸。肥胖会导致妊娠期间的慢性低度炎症，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，在新生儿脑损伤的实验模型中，普遍存在的一个限制是，动物通常被喂以低脂肪的食物，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，我们比较了在单侧脑缺氧缺血后，饲喂低脂饮食的母鼠后代与来自脂肪的34%卡路里的饮食的结果。高脂饮食子代降低了血清和脑内n3脂肪酸含量，循环单核细胞比例显著增加。在出生后第7天(P7)，两个饮食组的幼鼠同时接受缺氧缺血损伤。在高脂饮食组，我们发现在1或4周的恢复后，死亡率增加，感觉运动功能变差。这项建议的目的是确认这些趋势，并检验以下假设，即脑髓细胞表型和功能中的促炎开关是这些影响的基础机制，以及高脂肪饮食不成比例地增加脑白质损伤。研究将在单侧颈动脉引起的新生儿缺氧缺血性脑损伤模型中进行。 7日龄大鼠结扎和暴露于8%氧气。该模型的优点包括能够通过改变缺氧持续时间来滴定损伤的严重程度，以及结合多种互补的、可量化的功能和病理结果测量的可行性。本研究的目的是：(1)在缺氧缺血脑损伤的新生啮齿动物模型中，比较妊娠和哺乳期饲喂低脂肪(17%)和高脂肪(34%)饲料的母鼠后代的感觉运动功能和神经病理学结果。(Ii)确定孕期和哺乳期的母亲高脂饮食是否会诱导其后代血液和脑中的促炎性髓系细胞表型和功能。这一系列研究将为未来的临床前和临床研究提供必要的基础，将我们的新的初步结果转化为与现代美国人口相关的公共卫生措施、人类产妇饮食干预或新生儿治疗方案。

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.