Natural Killer Cell Deficiencies in Aging Mice

衰老小鼠的自然杀伤细胞缺陷

• 批准号: 8910611
• 负责人: Luis J Sigal
• 金额: $ 38.96万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2015-10-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910611
• 关键词: Activated Natural Killer Cell; Adhesions; Age; Aging; Animal Model; Animals; Biological Markers; Biological Process; Blood; Bone Marrow; Cell Aging; Cell Communication; Cell Maturation; Cell physiology; Cessation of life; Chimera organism; Collagen; Collagen Gene; Collagen Type I; Communicable Diseases; Defect; Disease; Epithelial; Functional disorder; Gene Frequency; Genetic; Health; Hematogenous; Human; Incidence; Individual; Infection; Infection Control; Infectious Ectromelia; Integrin Binding; Knowledge; Link; Literature; Liver; Mesenchymal; Microscopy; Mouse Pox Virus; Mouse Strains; Mus; Natural Killer Cells; Organ; Orthopoxvirus; Pathologic Processes; Patients; Peripheral; Physiological; Predisposition; Production; Radio; Research Design; Resistance; Resistance to infection; Risk; Role; Route; Solid; Staging; Stromal Cells; Surface; Symptoms; Systemic disease; Testing; Textbooks; Viral; Virus; Virus Diseases; Work; age related; aged; base; cell age; cell motility; follow-up; improved; lymph nodes; migration; mouse model; novel; pathogen; research study; type I collagen receptor

DESCRIPTION (provided by applicant): It is well established that a consequence of aging is an increased risk of infection related diseases and death. However, most work to date on aging and resistance to viral disease is correlative, because it does not reproduce the condition of increased susceptibility to a viral disease following a primary infection with naturally pathogenic viruses. We have previously shown that during infection with the mouse pathogen ectromelia virus (ECTV), young C57BL/6 (B6) mice survive the infection without symptoms of systemic disease because their natural killer cells (NKC) migrate to the draining lymph node (D-LN) and curb viral dissemination. Conversely, aged B6 mice succumb to the infection because their NKC fail to migrate to the D-LN and the virus spreads rapidly to vital organs. Further, we showed that the lack of NKC migration is intrinsic to the NKC, because adoptively transferred NKC from aged mice did not accumulate in the D-LN of young hosts, while NKC from young mice accumulated in the D-LN of aged hosts, protecting them from lethality. Thus, we established a direct link between migration defects of NKC in the aged and decreased resistance to an infection. More recently, we determined that the NKC in aged mice are deficient due to their improper maturation in the bone marrow. We will now follow up these observations in two Specific Aims. In Aim 1, we will determine why the migration of NKC is impaired, identify other defects of NKC in aged mice and determine the generality of our findings. In Aim 2, we will investigate why NKC in aged mice fail to properly mature in the bone marrow. Because many infectious diseases in humans spread systemically via LNs and NKC-deficient patients have significantly increased incidence of viral infections, it is possible that a defective NKC maturatin and migration also contributes to the increased susceptibility of older people to at least some viruses. Our mouse model provides a unique avenue to investigate NKC dysfunctions with strong potential to advance our knowledge on causes of increased susceptibility to viral disease that we believe should be translatable to humans.

描述（由申请人提供）： 众所周知，衰老的后果是感染相关疾病和死亡的风险增加。然而，迄今为止关于衰老和对病毒性疾病的抵抗力的大多数工作是相关的，因为它不能再现在自然致病性的原发性感染后对病毒性疾病的易感性增加的状况。 病毒我们以前已经表明，在感染小鼠病原体肢端病病毒（ECTV）期间，年轻的C57 BL/6（B6）小鼠在感染后存活，没有全身性疾病的症状，因为它们的自然杀伤细胞（NKC）迁移到引流淋巴结（D-LN）并抑制病毒传播。相反，老年B6小鼠死于感染，因为它们的NKC未能迁移到D-LN，病毒迅速扩散到重要器官。此外，我们表明NKC迁移的缺乏是NKC固有的，因为从老年小鼠过继转移的NKC不会在年轻宿主的D-LN中积累，而来自年轻小鼠的NKC在老年宿主的D-LN中积累，保护它们免于致死。因此，我们建立了老年人NKC迁移缺陷与感染抵抗力下降之间的直接联系。最近，我们确定老年小鼠中的NKC由于其在骨髓中的不适当成熟而缺乏。我们现在将在两个具体目标中跟进这些观察结果。在目标1中，我们将确定为什么NKC的迁移受损，确定老年小鼠NKC的其他缺陷，并确定我们的研究结果的一般性。在目标2中，我们将研究为什么老年小鼠的NKC不能在骨髓中正常成熟。由于人类中的许多传染病通过LN全身传播，并且NKC缺陷患者的病毒感染发生率显著增加，因此有可能NKC成熟和迁移缺陷也导致老年人对至少某些病毒的易感性增加。我们的小鼠模型提供了一种独特的途径来研究NKC功能障碍，具有很强的潜力来提高我们对病毒性疾病易感性增加的原因的认识，我们认为这些原因应该可以转化为人类。