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: 7672231
• 负责人: RICHARD L GUERRANT
• 金额: $ 33.76万
• 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/7672231
• 关键词: Address; Affect; Alleles; Alzheimer' 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

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贫民窟（棚户区）儿童早期腹泻和营养不良与认知发育、身体健康和生长受损的重要联系。在发现高级执行功能和语义流畅性的“阿尔茨海默病样”缺陷受到的影响最大之后，我们又发现了“阿尔茨海默病基因”APOE4与防止认知发育障碍之间的惊人联系。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育影响的持久损害产生最大影响，这种影响在缺乏“保护性”APOE4等位基因的个体中尤为突出，而特定的微量营养素干预可以改善这种影响。为了直接验证我们的假设，即肠道和认知障碍与ApoE有关，以及特定的微量营养素可以改善这些影响，并研究其中的潜在机制，我们在巴西塞阿拉联邦大学（UFC）和弗吉尼亚大学（UVa）分别建立了野生型和ApoE敲除了小鼠的早期营养不良、生长和认知发育的小鼠模型。此外，通过与杜克大学的同事进行新的协同合作，我们可以使用人类APOE4靶向替代“敲入”小鼠来专门检查APOE4的作用，以“关闭回路”我们的假设，并直接评估APOE4是否以及如何保护肠道和营养不良的认知影响，这些研究将直接影响整个发展中地区儿童的最佳健康和发展。因此，我们的具体目标是在小鼠模型中定义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，该模型使用远交和近交野生型、ApoE敲除（ko）和人类ApoE4靶向替代“敲入”C57BI小鼠。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生的研究来确定对肠道和大脑组织学和成熟的影响。我们将寻求确定肠道和大脑中这些影响的潜在机制，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。