Natural Killer Subset Senescence and Clonality in Aging

描述（由申请人提供）：自然杀伤（NK）细胞使用KIR和CD 94/NKG 2A受体检测已下调MHC I类分子的感染细胞和癌细胞。NK细胞功能下降与老年人感染和健康状况不佳有关，但对老年人NK受体表达或群体动态知之甚少。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NK细胞的种群动态和衰老中的更替，特别是当它们与NK受体表达的年龄相关变化有关时。在我们新的初步数据的支持下，我们的中心假设是NK受体表达的年龄相关变化是由NK发育的变化引起的，这反过来又改变了NK功能和周转。这种转移平衡的一个特征是具有受限受体库的NK细胞的积累。拟议研究的理由是，更好地了解NK群体动态和NK受体表达的变化可能使我们能够在健康和不健康的衰老中操纵先天免疫。我们的具体目标是研究人类NK细胞群体动态，因为它们与KIR和CD 94/NKG 2受体表达和其他定义的NK亚群有关。我们将1。检测NK细胞亚群复制潜能和衰老标志物随年龄增长的表达; 2.测量来自年轻和老年成人受试者的KIR+和NKG 2A + NK细胞的周转率，3.评估年轻和老年受试者中具有受限受体库的NK亚群的发生率，并将严格测试NK亚群是多克隆还是单克隆。我们的方法是创新的。我们已经记录了NK受体之间的相互关系，在老化，我们已经证明了第一次，NK亚群与受限制的受体库被发现在健康的老年人。我们期望这项拟议的研究将严格检验我们的假设，并导致未来对NK亚群发育、功能、增殖和衰老的明确研究。

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.