Natural Killer Subset Senescence and Clonality in Aging

描述(申请人提供)：自然杀伤(NK)细胞使用KIR和CD94/NKG2A受体来检测感染细胞和MHC I类分子下调的癌细胞。老年人NK细胞功能下降与感染和健康状况不佳有关，但对老年人NK受体的表达或种群动态知之甚少。我们的长期目标是操纵NK细胞以促进健康衰老。我们目前的目标是研究人类自然杀伤细胞在衰老过程中的种群动态和更替，特别是当它们与年龄相关的NK受体表达的变化有关时。在我们新的初步数据的支持下，我们的中心假设是，与年龄相关的NK受体表达的变化是由NK发育的变化引起的，这反过来又改变了NK的功能和周转。这种平衡变化的一个特征是NK细胞积累了受限制的受体谱系。这项研究的理论基础是，更好地了解NK群体动态和NK受体表达的变化可能会让我们在健康和不健康的衰老过程中操纵先天免疫。我们的特殊目的是研究人类NK细胞种群的动态变化，因为它们与KIR和CD94/NKG2受体的表达以及其他已定义的NK亚群有关。我们将1.检测NK细胞亚群中衰老标志物随年龄增长的复制潜能和表达情况，2.测定青年和老年受试者KIR+和NKG2A+NK细胞的周转率，3.评估具有限制性受体谱系的NK亚群在青年和老年受试者中的发生率，并严格检验NK亚群是多克隆的还是单克隆的。我们的方法是创新的。我们已经记录了NK受体与衰老之间的相互关系，并首次证明在健康的老年人中发现了具有受限受体谱系的NK亚群。我们期望，这项拟议的研究将严格检验我们的假设，并导致明确的未来研究NK亚群的发展，功能，增殖和衰老。

DESCRIPTION (provided by applicant): Natural killer (NK) cells use KIR and CD94/NKG2A receptors to detect infected cells and cancer cells that have downregulated MHC class I molecules. Declining NK cell function is associated with infection and poor health in the elderly, but little is know about NK receptor expression or population dynamics in the elderly. OUR LONG-RANGE GOAL is to manipulate NK cells to promote healthy aging. Our CURRENT OBJECTIVE is to study human NK population dynamics and turnover in aging, especially as they relate to age related shifts in NK receptor expression. Supported by our novel preliminary data, our CENTRAL HYPOTHESIS is that an age related change in NK receptor expression is caused by a change in NK development and this in turn alters NK function and turnover. A feature of this shifting balance is the accumulation of NK cells with restricted receptor repertoire. The RATIONALE of the proposed research is that a better understanding of NK population dynamics and shifting NK receptor expression may allow us manipulate innate immunity in healthy and unhealthy aging. Our SPECIFIC AIM is to investigate human NK population dynamics as they relate to KIR and CD94/NKG2 receptor expression and other defined NK subsets. We will 1. test the replication potential and expression of senescence markers in NK subsets with aging, 2. measure turnover rates in KIR+ and NKG2A+ NK cells from young and elderly adult subjects, 3. evaluate the incidence of NK subpopulations with restricted receptor repertoire in young and elderly subjects and will rigorously test whether the NK subpopulations are polyclonal or monoclonal. Our approach is INNOVATIVE. We have documented a reciprocal relationship between NK receptors in aging and we have demonstrated for the first time that NK subpopulations with restricted receptor repertoire are found in healthy elderly people. It is our EXPECTATION that the proposed study will rigorously test our hypotheses and lead to definitive future studies on NK subset development, function, proliferation, and senescence.