Protective role of creb-binding protein in maturation and aging

描述(由申请人提供)：我们提出CBP和相关的组蛋白乙酰转移酶(HAT)活性在成熟过程中迅速下降的功能是结束一系列关键的组织时期，特别是在大脑中，但由于降低了转录灵活性，导致在衰老过程中失去适应能力。我们在研究中证明了CBP复合体在衰老过程中的保护作用的重要性，研究表明，这种复合体是由饮食限制诱导的，阻止这种诱导可以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作为一种青少年保护因子的作用机制，成熟后CBP的耗竭会导致与年龄相关的损害。一、成熟过程中CBP-HAT活性下降的原因和后果。断奶后的特定脂类可以减少成熟期CBP的快速下降。因此，我们建议评估出生时、出生后1、2、3和4周雄性和雌性小鼠的几个脑区、肝脏和空肠中CBP和其他转录因子或组蛋白乙酰化的mRNA；小鼠将断奶到正常的高碳水化合物饮食或高脂肪饮食，因为HDAC抑制剂可以补偿HAT活性的降低，并且我们已经证明HDAC抑制剂可以延长寿命并改善一些与年龄相关的损伤，另外一组小鼠将接受HDAC抑制剂的治疗。成熟期间饮食的长期后果母乳喂养产生的长期健康益处可能是通过牛奶中的脂类来调节的。因此，我们建议评估断奶小鼠在3个月大之前是否会在CBP转录复合体中产生永久性的升高，并伴随着组蛋白乙酰化和适应能力(记忆、节律和对营养剥夺的反应)的改善。用HDAC抑制剂逆转6个月和16个月大的小鼠的年龄相关损伤，将用HDAC抑制剂治疗2个月，并将评估组蛋白乙酰化和记忆、节律以及对营养剥夺的反应。我们预计，断食高脂饮食并使用HDAC抑制剂治疗将会改善组蛋白乙酰化和衰老过程中的适应能力。拟议中的研究涉及评估两种干预措施--断奶后的高脂肪饮食，以及我们已证明在模式生物中具有保护性的药物--是否会在衰老过程中起到保护作用。如果成功的人体试验可能随之而来。

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.