Latexin's role in parsing stem cells

Latexin 在解析干细胞中的作用

• 批准号: 7748922
• 负责人: GARY VAN ZANT
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748922
• 关键词: Accounting; Adolescent; Adopted; Adult; Age; Aging; Apoptosis; Bone Marrow; C57BL/6 Mouse; Categories; Cell Aging; Cell Count; Cells; Childhood; Chronology; Conscious; CpG Islands; CpG dinucleotide; DNA Damage; Data; Development; Diet; Elderly; Embryo; Embryonic Development; Ensure; Epigenetic Process; Event; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Health Care Costs; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Knock-out; Knockout Mice; Life; Life Style; Longevity; Mammals; Methylation; Modeling; Mouse Strains; Mus; Organ; PC3.1 antigen; Pathway interactions; Pattern; Physiological; Play; Population; Population Sizes; Property; Proteins; Quality of life; Reactive Oxygen Species; Regulation; Relative (related person); Role; Smoking; Specificity; Staging; Stem Cell Factor; Stem cells; Teenagers; Tissues; Transgenic Mice; Uncertainty; Unconscious State; adult stem cell; age effect; age related; base; cell age; emerging adult; falls; fetal; functional decline; healthy aging; knockout animal; neglect; novel; progenitor; promoter; stem cell population; tool; trait; young adult

DESCRIPTION (provided by applicant): Juvenile factors that have potential effects on aging are myriad, but fall into two broad categories: conscious and unconscious. An example of the former is taking up smoking as a pre-teen or adopting other dangerous lifestyles when young that are known, at least on a statistical basis, to shorten lifespan. Of course, not all conscious decisions have detrimental effects. Many decisions, about diet for example, could promote healthy aging and a longer lifespan. This application is concerned with the "unconscious" category of factors detectable at early developmental stages that influence, either positively or negatively, not only overall lifespan, but the quality of life with accumulating years. We focus on the number and functional capabilities of adult stem cells and the factors that parse their limited numbers and functional properties over a lifetime. Our underlying hypothesis is that quantitative and qualitative alterations in stem cells influence lifespan and successful aging. We study hematopoietic stem cells as a paradigm adult stem cell population and have shown age-related changes in stem cell number and function in mice. Moreover, we have sought genetic determinants of stem cell properties that have an effect during aging. This proposal narrowly focuses on a quantitative trait, the number of stem cells at a young age, also correlated with lifespan. By utilizing the tools afforded by modern mouse genetics, we have identified a quantitative trait gene and its protein product, latexin, that is important in mammals in parsing stem cells. In this application we propose to investigate the pattern of latexin expression in hematopoietic stem cells during embryonic development and at multiple points during adulthood and correlate these data with quantitative and qualitative parameters of stem cells, and organismal longevity. An important tool we will make use of in these studies is latexin knockout mice which we are currently generating. In constitutive knockout animals we will study the effects on stem cells and aging when latexin is absent throughout development and adulthood. In conditional knockout mice we will determine when during development and young adulthood the presence of latexin is critical. Moreover, the conditional knockouts will enable us to study the tissues in which latexin's expression is important, and when. Lastly, we investigate the genetic and epigenetic regulation of latexin expression segmentally, at different stages of organismal development and adulthood. Preliminary data demonstrate in specific mouse strains, that latexin expression is differentially regulated by both polymorphisms in the promoter and differential methylation of CG dinucleotides comprising a CpG island in the latexin promoter. In aggregate, these descriptive and mechanistic studies will provide definitive information on the basic premise that adult stem cells influence aging and, in particular, the role that latexin plays as a mechanistic factor in this pathway. The median age of the U.S population continues to increase and will accelerate in the upcoming few decades. Healthy aging is thus a national priority, especially given the rapidly rising costs of health care. Yet many of the physiological events occurring during development and early in childhood that have serious repercussions on the quality of life later, are poorly understood. We believe that the regulation of stem cells and particularly the parsing of these populations chronologically is an important and neglected aspect of this quest. The proposed studies, based on firm preliminary results, specifically focus on the role of a novel stem cell regulator, latexin, on the hematopoietic stem cell population in a mammalian species, the mouse.

描述(申请人提供)：对衰老有潜在影响的青少年因素很多，但分为两大类：有意识的和无意识的。前者的一个例子是，在十几岁之前就开始吸烟，或者在年轻时采取其他危险的生活方式，至少在统计基础上，这些生活方式会缩短寿命。当然，并不是所有有意识的决定都会产生有害的影响。例如，许多关于饮食的决定可能会促进健康的衰老和更长的寿命。这一应用涉及在早期发育阶段可以检测到的“无意识”因素类别，这些因素不仅对整体寿命产生积极或消极的影响，而且随着年龄的增加而影响生活质量。我们专注于成体干细胞的数量和功能能力，以及分析其有限数量和一生中功能特性的因素。我们的基本假设是，干细胞的数量和质量变化会影响寿命和成功的衰老。我们将造血干细胞作为一个典型的成人干细胞群体进行研究，并在小鼠中显示了干细胞数量和功能的年龄相关变化。此外，我们还寻找在衰老过程中会产生影响的干细胞特性的遗传决定因素。这一建议狭隘地侧重于一种数量性状，即年轻时干细胞的数量，也与寿命相关。通过利用现代小鼠遗传学提供的工具，我们已经确定了一个数量性状基因及其蛋白产物，Latexin，它在哺乳动物解析干细胞时起着重要的作用。在这项应用中，我们建议研究在胚胎发育期间和成年后多个时间点造血干细胞中乳胶蛋白的表达模式，并将这些数据与干细胞的数量和质量参数以及生物寿命相关联。我们将在这些研究中使用的一个重要工具是我们目前正在培育的乳胶蛋白基因敲除小鼠。在结构性基因敲除动物中，我们将研究在整个发育和成年过程中缺乏乳胶蛋白对干细胞和衰老的影响。在条件基因敲除小鼠中，我们将确定在发育和成年期，乳胶蛋白的存在是至关重要的。此外，条件性基因敲除将使我们能够研究在哪些组织中Latexin的表达是重要的，以及何时表达。最后，我们研究了在生物体发育和成体的不同阶段，乳胶蛋白表达的遗传和表观遗传调控。初步数据表明，在特定的小鼠品系中，Latexin的表达受到启动子中的多态性和在Latexin启动子中包含CpG岛的CG二核苷酸的差异甲基化的调节。总而言之，这些描述性和机械性的研究将提供关于成体干细胞影响衰老的基本前提的明确信息，特别是乳胶蛋白在这一途径中作为机械因素所起的作用。美国人口的年龄中值继续增加，并将在接下来的几十年里加速。因此，健康老龄化是国家的优先事项，特别是考虑到医疗保健成本的迅速上升。然而，许多发生在发育期间和童年早期的生理事件对后来的生活质量产生了严重影响，人们对这些事件知之甚少。我们认为，对干细胞的调控，特别是按时间顺序分析这些群体，是这一探索中一个重要而被忽视的方面。拟议的研究基于明确的初步结果，特别关注一种新的干细胞调节因子--乳胶蛋白--对哺乳动物物种小鼠的造血干细胞群体的作用。