Dietary Restriction, GH/IGF-I & Mechanisms of Differential Cellular Protection

描述（由申请人提供）：我们建议将来自洛杉矶不同学科、部门和大学的实验室聚集在一起，研究将饮食限制和饥饿与细胞保护和衰老联系起来的分子机制。这些研究将有助于确定治疗和预防多种衰老疾病的药物和干预措施。该计划项目包括3个主要项目，动物和生物统计学核心和行政核心。共同目标是：a）确定可以保护正常细胞和器官免受内源性和外源性毒素的影响的饮食干预和分子途径，重点关注年龄依赖性氧化DNA和蛋白质损伤以及寿命，B）理解细胞和生物体衰老的潜在机制，重点关注饥饿、生长因子依赖性信号传导、氧化和内质网（ER）应激，c）测试以下假设：通过饥饿、基因操作和药物调节抗衰老途径可以导致正常细胞和癌细胞对毒素的不同保护，并延长寿命。PI汇集了专业知识的最佳组合，范围从遗传学和饥饿依赖性调节衰老和抗应激的分子生物学，重点是IGF-I，IGFBPs及其信号传导途径，到内质网应激反应系统的知识及其与衰老和疾病的联系，以及与衰老生物学相关的高度挑战性程序和大规模动物研究的经验。每个PI的独特背景和他们之间的密切合作已经产生并将继续产生新的想法，以解决生长因子，抗压力，衰老和疾病之间非常复杂的联系。每个PI贡献的各种模型系统、转基因细胞和小鼠、试剂和技术专长无疑正在以独立研究无法实现的方式加速研究进展。

DESCRIPTION (provided by applicant): We propose to bring together laboratories from different disciplines, departments, and universities in Los Angeles to study the molecular mechanisms linking dietary restriction and starvation to cellular protection and aging. These studies will contribute to the identification of drugs and interventions to treat but also prevent multiple diseases of aging. The program project consists of 3 major projects, an Animal and Biostatistics Core and an Administrative Core. The common goals are to: a) identify dietary interventions and molecular pathways that can protect normal cells and organs against both endogenous and exogenous toxins with focus on age-dependent oxidative DNA and protein damage and life span, b) understand the underlying mechanisms of cellular and organismal aging with focus on starvation, growth factors-dependent signaling, oxidative and endoplasmic reticulum (ER) stress, c) test the hypothesis that the modulation of anti aging pathways by starvation, genetic manipulations and drugs can result in differential protection of normal and cancer cells against toxins and extend longevity. The PIs bring together an optimal combination of expertise ranging from those in the genetics and molecular biology of starvation-dependent modulation of aging and stress resistance with focus on IGF-I, IGFBPs, and their signaling pathways, to knowledge of endoplasmic reticulum stress response systems and their link to aging and diseases, to experience with highly challenging procedures and large scale animals studies related to the biology of aging. The unique background of each PI and the close collaborations between them has generated and will continue to generate novel ideas to address the very complex link between growth factors, stress resistance, aging, and diseases. The variety of model systems, genetically modified cells and mice, reagents, and technical expertise contributed by each PI is undoubtedly accelerating the research progress in a way that could not be achieved by independent studies.