Epigenetics of Aging and Age-associated Diseases

描述（由申请方提供）：所有动物均发生细胞老化以及体细胞和组织衰老。在后生动物中，衰老包括可再生组织的再生能力降低，这是由组织干细胞和祖细胞群的增殖和分化改变引起的。此外，还研究了一些模式生物，包括酵母、S.酿酒酵母，已经取得了显着的见解分子途径参与老化和衰老。这些变化包括基因组的变化，如端粒缩短，异染色质结构和功能的改变，以及基因表达的深刻变化。我们的假设是，表观遗传调控可能是这些与年龄相关的基因组结构和功能变化的关键决定因素。我们将集中在两个方面的染色质调控：组蛋白的翻译后修饰，和伴侣介导的组装成核小体支架的组蛋白变体。我们将使用几种模型：芽殖酵母母细胞的复制寿命限制和由端粒缩短引起的酵母衰老，以及哺乳动物骨髓来源的间充质祖细胞的衰老和分化以及骨组织的老化。这些项目通过两个主要实验重点的合作研究联系在一起：组蛋白去乙酰化酶Sir 2在酵母衰老和衰老中的功能，以及组蛋白伴侣HIRA/ASF 1a/UBN 1在调节骨细胞分化和衰老中的作用。首要的主题是，衰老，衰老和组织分化相关的一个强大的表观遗传调控组件。我们结合的初步数据支持这些目标，并提供了几个独特的和协同的途径，以解决主要的细胞和组织衰老的表观遗传问题。这些关键问题是：（1）Sir 2的活性、调节和定位是否直接参与酵母的复制老化和衰老？组蛋白H4 K16 ac是Sir 2的关键底物吗？(2)在体外改变Sir 2活性的小分子能否在体内改变衰老/衰老的动力学？(3)HIRA/ASF 1a在骨髓间充质祖细胞分化过程中对染色质结构的调控中起什么作用？(4)ASF 1/HIRA/组蛋白三聚体复合物的结构是什么？与染色质蛋白Ubn 1相关的HIRA的结构是什么？这些结构/功能的见解如何用于增强我们对细胞衰老和组织衰老的理解？人类疾病越来越多地与表观遗传途径有关。我们的项目将为驱动真核生物衰老的表观遗传调控的分子基础提供新的见解，并将产生这些途径的新型小分子调节剂。由于表观遗传改变是可逆的，这些研究有可能开发治疗药物和靶点，以减轻衰老和年龄相关疾病的衰弱方面。

DESCRIPTION (provided by applicant): Cellular aging and senescence of somatic cells and tissues occurs in all animals. In metazoans, aging consists of decreased regenerative capacity of renewable tissues, resulting from altered proliferation and differentiation of tissue stem and progenitor cell populations. In addition, certain model organisms, including the yeast, S. cerevisiae, have yielded remarkable insights into molecular pathways involved in aging and senescence. These include genomic changes such as telomere shortening, altered heterochromatic structure and function, and profound changes in gene expression. Our hypothesis is that epigenetic regulation is likely to be a key determinant underlying these age-associated changes in genomic structure and function. We will focus on two aspects of chromatin regulation: post-translational modifications of histone proteins, and chaperone-mediated assembly of histone variants into the nucleosomal scaffold. We will use several models: replicative lifespan-restriction of budding yeast mother cells and yeast senescence caused by telomere shortening, as well as senescence and differentiation of mammalian bone marrow-derived mesenchymal progenitor cells and aging of bone tissue. The projects are linked through collaborative studies of two major experimental focuses: the histone deacetylase Sir2 function in yeast aging and senescence, and the role of histone chaperones HIRA/ASF1a/UBN1 in regulating bone cell differentiation and senescence. The overarching theme is that aging, senescence and tissue differentiation are related by a strong epigenetic regulatory component. Our combined preliminary data support these aims and offer several unique and synergistic avenues to address major epigenetic questions of cellular and tissue aging. These key questions are (1) Is Sir2 activity, regulation, and localization directly involved in yeast replicative aging and senescence? Is histone H4 K16ac the key substrate of Sir2 related to its role in aging/senescence? (2) Can small molecules that alter Sir2 activity in vitro, alter the kinetics of aging/senescence in vivo? (3) What is the role of HIRA/ASF1a in regulation of chromatin structure during differentiation of bone marrow-derived mesenchymal progenitor cells? (4) What is the structure of the ASF1/HIRA/histone trimeric complex? What is the structure of HIRA in association with the chromatin protein Ubn1? How can these structure/function insights be used to enhance our understanding of cell senescence and tissue aging? Human disease is increasingly being linked to epigenetic pathways. Our project will provide new insights into the molecular basis of epigenetic regulation that drive eukaryotic aging, and will generate novel small molecule regulators of these pathways. Because epigenetic alterations are reversible, these studies have the potential to develop therapeutic agents and targets to alleviate debilitating aspects of aging and age-related diseases.