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

基本信息

批准号：
7929154
负责人：
RICHARD L GUERRANT
金额：
$ 3.51万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929154
关键词：
Address Affect Alleles Alzheimer&apos s Disease Animals Apolipoprotein E Apoptosis Area Arginine Behavior Behavioral Bioinformatics Biometry Blood - brain barrier anatomy Brain Brain Diseases Brain region Brazil Cell Proliferation Child Child Development Cognitive Collaborations Corticosterone Development Diarrhea Dipeptides Employee Strikes Exhibits Felis catus Gene Cluster Gene Expression Genes Genetic Research Genomics Glutamine Growth Healed Health Hippocampus (Brain)Histologic Histology Human Hydrocortisone Impaired cognition Impairment Individual Insulin-Like Growth Factor I Intervention Intestines Knock-in Mouse Knock-out Knockout Mice Laboratories Life Long-Term Effects Longevity Longitudinal Studies Malnutrition Methods Micronutrients Modeling Mus NIH Program Announcements Nutrient Outcome Permeability Physical Fitness Pilot Projects Play Proteins Recovery Relative (related person)Reporting Research Research Personnel Role Semantics Site Small Intestines Somatomedins Stress System Testing Tight Junctions Training Transgenic Mice Universities Virginia Weaning Zinc alanylglutamine apolipoprotein E-3 apolipoprotein E-4 base biological adaptation to stress brain morphology cell motility early childhood executive function feeding field study functional disability genetic epidemiology healing improved interdisciplinary collaboration maternal separation migration new technology postnatal programs promoter rapid growth response tool

项目摘要

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，我们发现巴西东北部贫民窟儿童的认知发展、身体健康和生长受损与幼儿期腹泻和营养不良存在重要关联。我们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”缺陷受影响最大，随后我们发现“阿尔茨海默氏症基因”APOE4 与预防认知发育障碍之间存在显着关联。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的持久损害产生最大影响，这种影响在缺乏“保护性”APOE4 等位基因的个体中更为严重，并且特定的微量营养素干预措施可以改善这种影响。为了直接检验我们的假设，即肠道和认知障碍涉及 ApoE，并且特定的微量营养素可以改善这些影响，并检查所涉及的潜在机制，我们在野生型和野生型中建立了早期营养不良、生长和认知发育的小鼠模型。 APOE 敲除小鼠分别是我们在巴西塞阿拉联邦大学 (UFC) 和弗吉尼亚大学 (UVa) 的合作项目。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 靶向替代“敲入”小鼠来专门检查 APOE4 的效果，以“闭合循环”我们的假设，并直接评估 apoE4 是否以及如何具有保护作用营养不良对肠道和认知的影响，这些研究将对整个发展中地区儿童的最佳健康和发育产生直接影响。因此，我们的具体目标是使用远交和近交野生型、ApoE 敲除 (ko) 和人类 ApoE4 靶向替代“敲除”小鼠模型来确定营养不良和特定微量营养素对肠道、大脑和认知发育的影响。在”C57BI 小鼠中。我们将使用免疫组织化学方法以及发育里程碑和行为个体发育的研究来定义对肠道和大脑组织学和成熟的影响。我们将寻求确定这些影响在肠道和大脑中的潜在机制，包括 IGF-1 的研究，并将检查谷氨酰胺、锌和精氨酸干预措施的影响。