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

描述(由申请人提供)：我们建议将洛杉矶不同学科、系和大学的实验室聚集在一起，研究饮食限制和饥饿与细胞保护和衰老之间的分子机制。这些研究将有助于确定治疗多种衰老疾病的药物和干预措施。该方案项目由三个主要项目组成，一个是动物和生物统计核心，另一个是行政核心。这些研究的共同目标是：a)确定能够保护正常细胞和器官免受内源性和外源性毒素伤害的饮食干预措施和分子途径，重点关注依赖年龄的氧化DNA和蛋白质损伤及寿命；b)了解细胞和组织衰老的潜在机制，重点关注饥饿、生长因子依赖的信号转导、氧化和内质网应激；c)测试以下假设：饥饿、基因操作和药物对抗衰老途径的调节可导致正常细胞和癌细胞免受毒素的不同保护，从而延长寿命。PI集合了各种专业知识的最佳组合，包括依赖饥饿调节衰老和应激抗性的遗传学和分子生物学方面的专业知识，重点是IGF-I、IGFBPs及其信号通路，以及内质网应激反应系统及其与衰老和疾病的联系的知识，以体验与衰老生物学相关的高挑战性程序和大规模动物研究。每个PI的独特背景以及它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、抗压能力、衰老和疾病之间非常复杂的联系。每个PI贡献的模型系统、转基因细胞和小鼠、试剂和技术专长的多样性，无疑正在以独立研究无法实现的方式加快研究进展。

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.