APOE and the Effects of Malnutrition on Cognitive and Intestinal Development

APOE 和营养不良对认知和肠道发育的影响

• 批准号: 7105283
• 负责人: RICHARD L GUERRANT
• 金额: $ 27.25万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105283
• 关键词: alleles; apolipoprotein E; behavior test; biological signal transduction; cognition disorders; diarrhea; disease /disorder model; executive function; genetically modified animals; growth /development; histology; immunocytochemistry; intestine disorder; laboratory mouse; malnutrition; physical fitness; semantics

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.

描述（由申请人提供）：在长期研究中，我们发现了巴西东北部的Favela（Shantytown）儿童的认知发展，身体健康和生长与幼儿腹泻和营养不良的重要关联。发现较高的执行功能和语义流利性最大的“阿尔茨海默氏症般的”赤字受到影响，然后我们发现了“阿尔茨海默氏症基因” APOE4的惊人关联，并避免了认知发展障碍。因此，我们假设幼儿期腹泻及其随之而来的营养不良通过对认知发育效果的持久损害对缺乏“保护性” APOE4等位基因的个体突显的认知发展效应产生了最大的影响，并且特定的微量营养干预措施可以改善这种效果。 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）分别。此外，通过与杜克大学的同事进行协同的新合作，我们可以专门检查APOE4的效果，使用人APOE4有针对性的替代品“敲击”小鼠“关闭循环”对我们的假设“关闭循环”，并直接评估APOE4是否以及如何保护对营养不良的肠道和认知能力的影响，这将导致儿童的发展，从而导致健康和发展的研究。因此，我们的具体目的是在使用杂种和近交野生型，APOE敲除（KO）和Human ApoE4靶向替换的“敲入” C57BI小鼠C57BI小鼠的鼠模型中定义营养不良和特异性微量营养素对肠道，大脑和认知发育的影响。我们将使用免疫组织化学方法以及对发展里程碑和行为本体发育的研究来定义对肠道和脑组织学的影响以及成熟。我们将寻求在肠道和大脑中确定这些作用的潜在机制，包括对IGF-1的研究，并将检查谷氨酰胺，锌和精氨酸干预的作用。