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

基本信息

批准号：
7934102
负责人：
CHARLES V MOBBS
金额：
$ 5.44万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7934102
关键词：
Acetylation Adolescent 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

项目摘要

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）：我们提出成熟过程中CBP和相关组蛋白乙酰基转移酶（HAT）活性的快速下降，这是结束一系列关键时期的功能，尤其是在大脑中，但通过降低转录柔韧性会导致衰减过程中的适应能力丧失。在研究过程中，我们证明了CBP复合物在衰老过程中的保护作用的重要性，这表明这种复合物是由饮食限制引起的，并且阻止这种诱导会阻止饮食限制的几种保护作用。因此，我们建议以更详细的机制检查CBP作为少年保护因素，其成熟后的耗竭会驱动与年龄相关的损害。 I.成熟过程中CBP帽活性下降的原因和后果。断奶后的特定脂质减少了成熟过程中CBP的快速减少。因此，我们建议在几个脑部肝脏中评估CBP和其他转录因子或组蛋白乙酰化的mRNA，以及出生时雄性和雌性小鼠的空肠，以及出生后的1、2、2、3和4周；由于HDAC抑制剂可以补偿降低的HAT活性，因此将小鼠断奶为正常的高碳水化合物饮食或高脂饮食，并且我们已经表明HDAC抑制剂会增加寿命并改善某些与年龄相关的损害，因此，另一组小鼠将用HDAC抑制剂治疗。 ii。饮食在成熟过程中的长期后果会产生牛奶中脂质介导的长期健康益处。因此，我们建议评估断奶小鼠在特定脂质的高饮食上是否会在CBP转录复合物中产生永久升高，并在衰老期间伴有组蛋白乙酰化和适应能力（记忆，节奏和对营养剥夺的反应）的伴随改善。 iii。 HDAC抑制剂与年龄相关的损伤的反转6个月和16个月大的小鼠将用HDAC抑制剂治疗2个月，组蛋白乙酰化和记忆，节奏以及对营养剥夺的反应。我们预计断奶在脂质中高饮食并用HDAC抑制剂处理将导致衰老期间改善组蛋白乙酰化和适应能力。拟议的研究涉及评估两种干预措施，即高脂饮食后的断奶以及我们在模型生物体中证明具有保护性的药物是否会在衰老期间具有保护作用。如果成功进行人类试验。