Protective role of creb-binding protein in maturation and aging

描述（由申请人提供）：我们提出成熟过程中CBP和相关组蛋白乙酰转移酶（HAT）活性的快速下降有助于结束一系列组织的关键时期，特别是在大脑中，但通过降低转录灵活性导致衰老过程中适应能力的丧失。我们在研究中证明了CBP复合物在衰老过程中的保护作用的重要性，表明该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作为少年保护因子的机制，该因子在成熟后的耗竭会导致年龄相关的损伤。成熟过程中CBP-HAT活性下降的原因和后果。断奶后的特定脂质降低了成熟时CBP的快速下降。因此，我们建议在雄性和雌性小鼠出生时，以及出生后1、2、3和4周，评估CBP mRNA和其他转录因子或组蛋白乙酰化在几个脑区、肝脏和空肠中的表达；小鼠将断奶为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抑制剂治疗。2。母乳喂养产生长期的健康益处，可能是由牛奶中的脂质介导的。因此，我们建议评估断奶小鼠在3个月大之前，是否会产生CBP转录复合物的永久性升高，同时在衰老过程中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。3。6个月和16个月大的小鼠将接受2个月的HDAC抑制剂治疗，并评估组蛋白乙酰化、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抑制剂治疗将改善组蛋白乙酰化和衰老过程中的适应能力。拟议的研究包括评估两种干预措施，断奶后的高脂肪饮食和一种我们已经证明对模式生物有保护作用的药物，是否会在衰老过程中产生保护作用。如果成功，可能会进行人体试验。

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.