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.
|Gao, Xin; Brown, Gregory K; Elliott, Michael R (2014) Joint modeling compliance and outcome for causal analysis in longitudinal studies. Stat Med 33:3453-65|
|Kiper, Carmen; Grimes, Barry; Van Zant, Gary et al. (2013) Mouse strain determines cardiac growth potential. PLoS One 8:e70512|
|Spokas, Megan; Wenzel, Amy; Brown, Gregory K et al. (2012) Characteristics of individuals who make impulsive suicide attempts. J Affect Disord 136:1121-5|
|Van Zant, Gary; Liang, Ying (2012) Concise review: hematopoietic stem cell aging, life span, and transplantation. Stem Cells Transl Med 1:651-7|
|Stirman, Shannon Wiltsey; Brown, Gregory K; Ghahramanlou-Holloway, Marjan et al. (2011) Participation bias among suicidal adults in a randomized controlled trial. Suicide Life Threat Behav 41:203-9|
|Waterstrat, Amanda; Liang, Ying; Swiderski, Carol F et al. (2010) Congenic interval of CD45/Ly-5 congenic mice contains multiple genes that may influence hematopoietic stem cell engraftment. Blood 115:408-17|
|Ryan, Marnie A; Nattamai, Kalpana J; Xing, Ellen et al. (2010) Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization. Nat Med 16:1141-6|