APOE and the Effects of Malnutrition on Cognitive and Intestinal Development

描述(申请人提供)：在长期研究中，我们在巴西东北部的贫民窟(棚户区)儿童中发现认知发展、身体健康和生长受损与儿童早期腹泻和营养不良的重要关联。在发现高级执行功能和语义流畅性方面的“类阿尔茨海默氏症”缺陷受到的影响最大后，我们随后发现“阿尔茨海默氏症基因”APOE4与认知发育障碍的保护作用之间存在显著的关联。因此，我们假设，儿童早期腹泻及其随之而来的营养不良通过对认知发展影响的持久损害而产生最大影响，这种影响在缺乏“保护性”APOE4等位基因的个体中更加突出，而特定的微量营养素干预可以改善这种影响。为了直接测试我们的假设，即肠道和认知损伤与ApoE有关，以及特定的微营养素可以改善这些影响，并检查相关的潜在机制，我们分别在巴西塞拉联邦大学(UFC)和弗吉尼亚大学(UVA)的合作中，建立了野生型和APOE基因敲除小鼠的早期营养不良、生长和认知发育的模型。此外，通过与杜克大学同事的协同新合作，我们可以使用人类APOE4靶向替换“敲入”小鼠来具体检验APOE4的效果，以“关闭”我们的假设，并直接评估apoE4是否以及如何保护肠道和认知免受营养不良的影响，这些研究将对整个发展中地区儿童的最佳健康和发展产生直接影响。因此，我们的具体目标是确定营养不良和特定的微量营养素对小鼠肠道、大脑和认知发育的影响，该模型使用近交系和野生型、ApoE基因敲除(Ko)和人类ApoE4靶向替换“敲入”C57BI小鼠。我们将使用免疫组织化学方法以及对发育里程碑和行为个体发育的研究来确定对肠道和大脑组织学和成熟度的影响。我们将寻求确定这些影响在肠道和脑中的潜在机制，包括对IGF-1的研究，并将检查谷氨酰胺、锌和精氨酸干预的影响。

DESCRIPTION (provided by applicant): In long-term studies, we have discovered important associations of impaired cognitive development, physical fitness, and growth with early childhood diarrhea and malnutrition in favela (shantytown) children in Northeast Brazil. Having found that an "Alzheimer's-like" deficit in higher executive function and semantic fluency were most affected, we then found a striking association of the "Alzheimer's gene," APOE4, with protection from the cognitive developmental impairments. Hence we postulate that early childhood diarrhea and its consequent malnutrition have their greatest impact via lasting impairment on cognitive development effects that are accentuated in individuals lacking the "protective" APOE4 allele and that specific micronutrient interventions can ameliorate this effect. In order to directly test our hypothesis that intestinal and cognitive impairments involve ApoE and that specific micronutrients can ameliorate these effects, and to examine potential mechanisms involved, we have established murine models of early malnutrition, growth, and cognitive development in both wild-type and APOE-knockout mice in our collaborations at the Federal University of Ceara (UFC) in Brazil and at the University of Virginia (UVa) respectively. Furthermore, with a synergistic new collaboration with colleagues at Duke University, we can specifically examine effects of APOE4 using human APOE4 targeted replacement "knock-in" mice to "close the loop" on our hypothesis and directly assess whether and how apoE4 is protective against intestinal and cognitive effects of malnutrition, studies that will have direct implications for the optimal health and development of children throughout developing areas. Hence our specific aims are to define the effects of malnutrition and specific micronutrients on intestinal, brain, and cognitive development in a murine model using outbred and inbred wild-type, ApoE knock-out (ko), and human ApoE4 targeted replacement "knock-in" C57BI mice. We will define the effects on intestinal and brain histology and maturation using immunohistochemical methods and studies of developmental milestones and behavioral ontogeny. We will seek to identify potential mechanisms of these effects in the intestine and brain including studies of IGF-1, and will examine the effects of glutamine, zinc, and arginine interventions.