The Role of the Wnt Signaling Pathway in Cellular Senescence and Aging

描述（由申请人提供）：在美国和其他发达国家，老龄化直接或间接地导致越来越多的死亡和使人衰弱的疾病（阿尔茨海默病、帕金森病、心脏病、癌症等），但在预防或治疗这些疾病方面却无能为力。该项目的目标是更多地了解衰老的原因，并发现治疗或延缓衰老的潜在治疗靶点。有许多提出的老化原因，包括大分子损伤积累，端粒缩短，和我们的重点：细胞衰老。最近的证据表明，Wnt信号可能在诱导细胞衰老中起作用，本项目旨在阐明这种情况发生的机制。第一步是通过比较来自年轻、年老和热量限制小鼠的选定组织类型的Q-PCR阵列的基因表达数据，确定哪些与Wnt信号有关的基因随着年龄的增长而改变表达。这将分别在脑、心脏和肺组织中进行，然后进行生物统计分析和染色质免疫沉淀（ChIP），以确定感兴趣基因的顺式调控位点和与这些位点结合的蛋白质。这个项目的第二部分侧重于因果关系而不是关联；随着年龄的增长而表达变化的基因及其调节因子（由ChIP决定）将在体外进行测试，以确定上调或下调它们是否能够诱导或延缓衰老。这不仅将证实Wnt信号导致衰老，从而也导致衰老，而且将提供一组可能对此负责的基因。在未来的研究中，这些基因的表达可以在体内以特定的组织方式改变，以确定这种修改是否可以延缓这些组织的衰老。这项研究与公共卫生有关，因为每个人都受到衰老的影响。直接地，它降低了生活质量，导致退化性和致命疾病的发展，老年人的护理费用，特别是在他们生命的最后一年，是天文数字。寻找新的治疗方法来延缓衰老的速度或治疗其影响不仅将提高大多数人的平均生活质量和健康寿命，而且还将降低社会的医疗保健成本

DESCRIPTION (provided by applicant): Aging is directly or indirectly responsible for an increasingly large amount of death and debilitating disease (Alzheimer's, Parkinson's, Heart Disease, Cancer, etc.) in this and other developed countries, yet there is little that can be done to prevent or treat these diseases. The goal of this project is to learn more about the causes of aging and to discover potential therapeutic targets for its treatment or retardation. There are many proposed causes for aging, including macromolecule damage accumulation, telomere shortening, and our focus: cellular senescence. Recent evidence has implicated a likely role of Wnt signaling in inducing cellular senescence, and this project seeks to elucidate the mechanism by which this occurs. The first step is to identify which genes that are involved in Wnt signaling have altered expression with age by comparing gene expression data from Q-PCR arrays of select tissue types in young, old and calorie-restricted mice. This will be done separately in brain, heart, and lung tissue, and followed by biostatistical analysis and chromatin immunoprecipitation (ChIP) to determine cis-regulatory sites of genes of interest and the proteins that bind to these sites. The second part of this project focuses on causation rather than association; the genes whose expression changes with age as well as their regulators (as determined by ChIP) will be tested in vitro to determine if up- or down-regulating them is able to induce or delay senescence. This will not only confirm that Wnt signaling causes senescence, and thereby aging as well, but will provide a set of genes that are likely to be responsible. In future studies the expression of these genes can be altered in vivo in a tissue specific manner to determine if this modification can retard aging of these tissues. This research is relevant to public health because everyone is affected by aging. Directly, it decreases quality of life and leads to the development of degenerative and deadly disease, and the cost of care of the elderly, particularly people in their last year of life, is astronomical. Finding novel therapies to retard the rate of aging or treat its effects will not only increase average quality of life and healthspan of most people, but will also decrease the cost of health care to society