Protective role of creb-binding protein in maturation and aging

creb结合蛋白在成熟和衰老中的保护作用

• 批准号: 7743460
• 负责人: CHARLES V MOBBS
• 金额: $ 40.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743460
• 关键词: Acetylation; Adolescent; Adult; Age; Age-Months; Aging; Alzheimer like pathology; Animal Model; Antibodies; Area; Attenuated; Behavior; Binding Proteins; Birth; Brain; Brain region; Breast Feeding; CREB-binding protein; CREB1 gene; Carbohydrates; Circadian Rhythms; Cognition; Complex; Cyclic AMP; Development; Diabetes Mellitus; Dictyostelium discoideum; Diet; Discipline of Nursing; Down-Regulation; Eating; Epinephrine; Escherichia coli; Estrogens; Exhibits; Exposure to; Fasting; Fatty Acids; Fatty acid glycerol esters; Female; Food; Gene Expression; Genes; Gestational Diabetes; Glucose; Health; Health Benefit; Hepatic Tissue; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase Inhibitor; Histone H3; Histone H4; Histone deacetylase inhibition; Histones; Hour; Human; Hypoglycemia; Hypothalamic structure; Impairment; Intestines; Language Development; Link; Lipids; Liver; Long-Term Effects; Longevity; Mammals; Mediating; Memory; Messenger RNA; Metabolic; Milk; Mothers; Mouse Strains; Mus; Neurosecretory Systems; Nutritional; Oleic Acids; Organ; Organizational Change; Oxidative Stress; PCAF gene; Pattern; Pharmaceutical Preparations; Phosphorylation; Physarum polycephalum; Protein Deficiency; Puberty; RNA Interference; Rattus; Regulation; Reporting; Resistance; Reversal Learning; Role; Series; Site; Sodium Butyrate; Source; Steroids; Stroke; System; Testosterone; Transferase; Visual Cortex; Water; Water consumption; Weaning; Western Blotting; age related; critical period; deprivation; design; dietary restriction; drinking water; feeding; flexibility; glycogenolysis; histone acetyltransferase; human CREBBP protein; improved; in vivo; jejunum; male; nutrition; post intervention; postnatal; prevent; protective effect; protein complex; protein expression; protein function; response; transcription factor

DESCRIPTION (provided by applicant): We propose the rapid decline of CBP and associated histone acetyltransferase (HAT) activity during maturation serves the function of ending a series of critical periods of organization, especially in the brain, but by reducing transcriptional flexibility leads to a loss of adaptive capacity during aging. We demonstrated significance of the protective effect of the CBP complex during aging in studies showing that this complex is induced by dietary restriction and that blocking this induction blocks several protective effects of dietary restriction. We therefore propose to examine in more detail mechanisms by which CBP functions as a juvenile protective factor whose depletion after maturation drives age-related impairments. I. Causes and consequences of decline in CBP-HAT activity during maturation. Specific lipids after weaning reduce the rapid reduction of CBP during maturation. We therefore propose to assess mRNA of CBP and other transcription factors or histone acetylation in several brain areas liver, and jejunum from male and female mice at birth, and 1, 2, 3, and 4 weeks after birth; mice will be weaned either to a normal high carbohydrate diet or a high-fat diet, Since HDAC inhibitors can compensate for reduced HAT activity, and we have shown that HDAC inhibitors increase lifespan and improve some age-related impairments, an additional group of mice will be treated with an HDAC inhibitor. II. Long-term consequences of diet during maturation Breastfeeding produces long-term health benefits possibly mediated by lipids in milk. We therefore propose to assess if weaning mice onto a diet high in specific lipids until 3 months of age will produce permanent elevation in the CBP transcriptional complex with concomitant improvement in histone acetylation and adaptive capacity (memory, rhythms, and response to nutritional deprivation) during aging. III. Reversal of age-related impairments by HDAC inhibitors 6- and 16-month-old mice will be treated with HDAC inhibitors for 2 months and histone acetylation and memory, rhythms, and response to nutritional deprivation will be assessed. We anticipate that weaning to a diet high in lipids and treating with HDAC inhibitors will cause improve histone acetylation and adaptive capacity during aging. The proposed studies involve assessing if two interventions, post-weaning to a high-fat diet, and a drug that we have shown to be protective in a model organism, will have a protective effect during aging. If successful human trials may ensue.

描述（由申请人提供）：我们提出在成熟过程中CBP和相关组蛋白乙酰转移酶（HAT）活性的快速下降起到结束一系列组织关键期的作用，特别是在大脑中，但是通过降低转录灵活性导致衰老过程中适应能力的丧失。我们证明了CBP复合物在衰老过程中的保护作用的重要性，研究表明这种复合物是由饮食限制诱导的，阻断这种诱导会阻断饮食限制的几种保护作用。因此，我们建议更详细地研究CBP作为青少年保护因子发挥作用的机制，其成熟后的耗竭驱动年龄相关的损伤。I.成熟过程中CBP-HAT活性下降的原因和后果。断奶后的特定脂质减少成熟过程中CBP的快速下降。因此，我们建议评估CBP和其他转录因子或组蛋白乙酰化的mRNA在几个脑区肝，空肠从雄性和雌性小鼠在出生时，出生后1，2，3，和4周;将小鼠断奶至正常的高碳水化合物饮食或高脂肪饮食。由于HDAC抑制剂可以补偿降低的HAT活性，我们已经证明HDAC抑制剂可以延长寿命，改善一些与年龄相关的损伤，另外一组小鼠将接受HDAC抑制剂治疗。二.母乳喂养可能通过牛奶中的脂质介导产生长期的健康益处。因此，我们建议评估，如果断奶小鼠到特定的脂质高的饮食，直到3个月的年龄将产生永久性的CBP转录复合物的升高，同时改善组蛋白乙酰化和适应能力（记忆，节奏，并响应营养剥夺）在老化过程中。三. HDAC抑制剂对年龄相关损伤的恢复将用HDAC抑制剂治疗6月龄和16月龄小鼠2个月，并评估组蛋白乙酰化和记忆、节律和对营养剥夺的反应。我们预计，断奶高脂饮食和HDAC抑制剂治疗将导致改善组蛋白乙酰化和老化过程中的适应能力。拟议的研究涉及评估两种干预措施，即断奶后高脂肪饮食和我们在模型生物中显示具有保护作用的药物，是否会在衰老过程中产生保护作用。如果人体试验成功的话。