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Aging Features in Mice with Conditional Expression of p16Ink4a

p16Ink4a 条件表达小鼠的衰老特征

基本信息

批准号：
8457013
负责人：
GREGORY H. ENDERS
金额：
$ 25.3万
依托单位：
FOX CHASE CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457013
关键词：
Address Age Aging Anemia Animal Model Antibiotics Attenuated Binding Biochemical Biological Assay Biological Markers Blood Vessels Body Weight decreased CDKN2A gene Cell Aging Cell Cycle Cell Cycle Arrest Cell Cycle Inhibition Cell Proliferation Cells Complex Cultured Cells Cultured Tumor Cells Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases DNA Damage Defect Developed Countries Disease Doxycycline Epithelial Cells Fostering Functional disorder G1 Arrest Genetic Markers Genomic Instability Hair Hematopoietic Hormonal Human Hypopigmentation In Vitro Individual Intervention Intestines Islets of Langerhans Knockout Mice Kyphosis deformity of spine Link Mediating Modeling Molecular Mus Natural regeneration Normal Cell Organ Outcome Pancreas Pathway interactions Pattern Phenotype Population Premature aging syndrome Process Proteins Regulation Relative (related person)Role Signal Transduction Skin Somatic Cell Stem cells System Testing Tetracyclines Time Tissues Trans-Activators Transgenes Transgenic Mice Tumor Cell Line Tumor Suppressor Proteins Work age related base cell type design follow-up genetic analysis in vivo inhibitor/antagonist insight intestinal epithelium mouse model neoplastic cell nerve stem cell normal aging novel postnatal research study response senescence stem stem cell niche tissue culture tissue regeneration tumor unpublished works

项目摘要

DESCRIPTION (provided by applicant): Aging is a complex process associated with gradual accumulation of macromolecular damage and loss of tissue regeneration. It has been difficult to tease out the relative contributions of these factors. p16Ink4a (p16) is a specific cell cycle inhibitor and tumor suppressor that accumulates with age and has been proposed as a biomarker of aging. p16 has been implicated in replicative senescence of many normal cell types in tissue culture, and we have shown that induction of p16 is sufficient to impose senescence in a cultured tumor cell line. Genetic analyses using p16-null mice revealed that p16 limits proliferation of progenitor cells in several tissues of older mice. However, whether p16 expression is sufficient to cause normal cells in vivo to arrest or senesce or to impose aging features is unknown. Surprisingly, none of p16's target Cyclin dependent kinases (Cdks) is essential in the mouse. To address these issues, we generated transgenic mice in which facile conditional expression of p16 is achieved by treatment with the antibiotic doxycycline (Dox). This simple system allows unprecedented control over cell proliferation. Induced p16 binds Cdk4 and inhibits proliferation of intestinal epithelial cells, including Lgr5+ intestinal stem cels. Broad induction in young mice imposes early aging phenotypes characterized by hair hypopigmentation and loss, weight loss, kyphosis, and anemia. We propose in Aim 1 to examine effects of selective p16 expression on aging parameters and cell proliferation in three different tissues--pancreatic islets, skin, and intestine. These tissues were selected for their ag-related phenotypes, evidence for roles for endogenous p16 in age-related dysfunction, established transactivator lines for Dox-sensitive transgene induction, and genetically validated histological markers of stem cells. In Aim 2, we will test whether the p16-imposed aging features and cell cycle arrest are reversible. These studies will establish that loss of cell proliferation s sufficient to confer aging phenotypes, challenging the paradigm that macromolecular damage is needed. Further, this work will explore the fundamental reversibility of such aging features while defining their relationship to stem/progenitor cell arrest and senescence.

描述（由申请人提供）：衰老是一个复杂的过程，与大分子损伤的逐渐积累和组织再生的丧失有关。很难梳理出这些因素的相对贡献。p16 Ink 4a（p16）是一种特异性细胞周期抑制因子和肿瘤抑制因子，随着年龄的增长而积累，并已被提议作为衰老的生物标志物。在组织培养中，p16与许多正常细胞类型的复制性衰老有关，并且我们已经表明，p16的诱导足以在培养的肿瘤细胞系中引起衰老。使用p16基因缺失小鼠的遗传分析显示，p16限制了老年小鼠几种组织中祖细胞的增殖。无论p16 表达是否足以引起体内正常细胞停滞或衰老或施加衰老特征尚不清楚。令人惊讶的是，p16的靶细胞周期蛋白依赖性激酶（Cdks）在小鼠中没有一个是必需的。为了解决这些问题，我们产生了转基因小鼠，其中p16的条件性表达是通过抗生素多西环素（Dox）治疗实现的。这个简单的系统允许对细胞增殖进行前所未有的控制。诱导的p16结合Cdk 4并抑制肠上皮细胞的增殖，包括Lgr 5+肠干细胞。在年轻小鼠中的广泛诱导施加了以毛发色素减退和损失、体重减轻、脊柱后凸和贫血为特征的早期衰老表型。我们在目的1中提出，研究选择性p16表达对三种不同组织（胰岛、皮肤和肠）中衰老参数和细胞增殖的影响。这些组织被选择为他们的年龄相关的表型，内源性p16在年龄相关的功能障碍的作用的证据，建立反式激活因子系的Dox敏感的转基因诱导，和遗传验证的干细胞的组织学标志物。在目标2中，我们将测试p16施加的衰老特征和细胞周期停滞是否是可逆的。这些研究将确定细胞增殖的丧失足以赋予衰老表型，挑战需要大分子损伤的范式。此外，这项工作将探索这种衰老特征的基本可逆性，同时定义它们与干/祖细胞停滞和衰老的关系。