Latexin's role in parsing stem cells

描述（由申请人提供）：对衰老有潜在影响的青少年因素有无数，但分为两大类：有意识和无意识。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，这些生活方式至少在统计学上是已知的，会缩短寿命。当然，并非所有有意识的决定都会产生有害影响。许多决定，例如关于饮食的决定，可以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检测到的“无意识”因素类别，这些因素不仅对总体寿命产生积极或消极影响，而且随着年龄的积累影响生活质量。我们专注于成体干细胞的数量和功能，以及分析其有限数量和功能特性的因素。我们的基本假设是，干细胞的数量和质量变化影响寿命和成功衰老。我们研究造血干细胞作为一个范例的成人干细胞群体，并已显示在小鼠干细胞数量和功能的年龄相关的变化。此外，我们还寻找了在衰老过程中起作用的干细胞特性的遗传决定因素。这个建议狭隘地集中在一个数量性状上，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质产物，latexin，这是重要的哺乳动物在解析干细胞。在本申请中，我们建议研究胚胎发育期间和成年期多个点的造血干细胞中Latexin表达的模式，并将这些数据与干细胞的定量和定性参数以及生物体寿命相关联。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生产的latexin敲除小鼠。在组成性基因敲除动物中，我们将研究在整个发育和成年期缺乏latexin时对干细胞和衰老的影响。在条件性基因敲除小鼠中，我们将确定在发育和成年早期，latexin的存在何时是关键的。此外，条件性基因敲除将使我们能够研究latexin表达重要的组织，以及何时表达。最后，我们调查的遗传和表观遗传调节latexin表达分段，在不同阶段的有机体的发展和成年。初步数据表明，在特定的小鼠品系，乳胶蛋白的表达差异调节的启动子中的多态性和CG二核苷酸的差异甲基化，包括在乳胶蛋白启动子的CpG岛。总之，这些描述性和机制研究将提供明确的信息的基本前提，成人干细胞影响衰老，特别是乳胶蛋白在这一途径中发挥的作用作为一个机制因素。美国人口的平均年龄继续增加，并将在未来几十年加速增长。因此，健康的老龄化是国家的优先事项，特别是考虑到医疗保健费用迅速上升。然而，人们对发育期间和儿童早期发生的许多对以后生活质量有严重影响的生理事件知之甚少。我们认为，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的一个重要而被忽视的方面。根据初步结果，拟议的研究特别关注一种新型干细胞调节剂latexin对哺乳动物物种小鼠造血干细胞群体的作用。

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.