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Hematopoietic stem cells and longevity

造血干细胞与长寿

基本信息

批准号：
9063473
负责人：
HANS-WILLEM E SNOECK
金额：
$ 39.35万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063473
关键词：
Address Adolescence Adult Affect Age Aging Agonist Alleles Animals Antigens Bone Marrow C57BL/6 Mouse Cells Chromosomes, Human, Pair 4 Code Congenic Mice Cytokine Signaling DBA/2 Mouse Data Elderly Failure Fetal Liver Funding Genes Genetic Variation Goals Health Hematopoiesis Hematopoietic Hematopoietic stem cells Human Immune response Immunity Immunologics Inbred Strains Mice Individual Infection Knock-in Ligands Link Longevity Maintenance Memory Modeling Mouse Strains Mus Organ PPAR gamma Play Process Production Publishing Quantitative Trait Loci Role Seeds Serum Signal Transduction Solid T cell regulation T cell response T-Cell Development T-Lymphocyte Testing Thymus Gland Transcriptional Activation Transforming Growth Factors Transgenic Mice Vaccines Variant Work age related aged cytokine immune function improved in vivo novel reproductive response

项目摘要

DESCRIPTION (provided by applicant): This proposal will focus on the functional consequences and underlying mechanisms of genetic variation in thymic involution, one of the hallmarks of immunologic aging. Vaccine failure in the elderly has been attributed at least in part to thymic involution because of a decreased pool of naive T cells leading to a decline in the capacity of aged individuals to mount immune responses to neoantigens. However, decreased production of naiive cells is associated with expansion of pre-existing memory cells. It is therefore possible that thymic involution and concomitant decline in naiive T cells production allows the establishment of a larger pool of memory cells capable or responding rapidly to infection, and thus providing improved immunity to adult individuals of reproductive age. Understanding the significance, functional consequences and underlying mechanisms of thymic involution is therefore of critical importance to human health. To identify mechanisms involved in thymic involution and establish models of delayed or accelerated thymic involution, we took advantage of genetic variation among inbred mouse strains. Our published and preliminary data indicate that a novel regulatory axis in hematopoiesis, consisting of Prdm16, which enhances the ligand- induced activity of peroxisome proliferator activated receptor-gamma (PPARγ) and through this activity regulates signaling by the cytokine TGF-ß2, affects thymic involution. Mouse strain-dependent coding variation in Prdm16 regulates the activity of this mechanism. To unequivocally address the role of this locus in vivo, we generated mice where the DBA/2 allele of Prdm16 was knocked in into the C57BL/6 background (B6Prdm16/D2 mice). In control mice, the C57BL/6 allele of Prdm16 was knocked into the C57BL/6 background (B6Prdm16/B6 mice). These mice, as well as Tgfb2+/- mice and congenic and transgenic mice with delayed or accelerated thymic involution, will be further examined in this proposal. The specific aims of this proposal are: Specific aim 1: To analyze thymic involution in B6Prdm16/D2 and B6Prdm16/B6 mice. Specific aim 2: To analyze the mechanism of delayed thymic involution. Specific aim 3: To analyze immune function in mice with delayed or accelerated thymic involution

描述（由申请人提供）：该提案将重点关注胸腺退化中遗传变异的功能后果和潜在机制，胸腺退化是免疫衰老的标志之一。老年人疫苗接种失败的至少部分原因是由于幼稚 T 细胞数量减少，导致老年人对新抗原产生免疫反应的能力下降，导致胸腺退化。然而，幼稚细胞产量的减少与预先存在的记忆细胞的扩张有关。因此，胸腺退化和随之而来的幼稚 T 细胞产量下降可能允许建立更大的记忆细胞池，这些细胞能够对感染做出快速反应，从而为育龄成年个体提供改善的免疫力。因此，了解胸腺复旧的意义、功能后果和潜在机制对于人类健康至关重要。为了确定胸腺复旧所涉及的机制并建立延迟或加速胸腺复旧的模型，我们利用了近交系小鼠品系之间的遗传变异。我们发表的初步数据表明，由 Prdm16 组成的造血作用中的一个新的调节轴，增强了过氧化物酶体增殖物激活受体-γ (PPARγ) 的配体诱导活性，并通过这种活性调节细胞因子 TGF-β2 的信号传导，影响胸腺复旧。 Prdm16 中的小鼠品系依赖性编码变异调节该机制的活性。为了明确阐明该基因座在体内的作用，我们生成了将 Prdm16 的 DBA/2 等位基因敲入 C57BL/6 背景的小鼠（B6Prdm16/D2 小鼠）。在对照小鼠中，Prdm16 的 C57BL/6 等位基因被敲入 C57BL/6 背景（B6Prdm16/B6 小鼠）。这些小鼠，以及Tgfb2+/-小鼠以及具有延迟或加速胸腺退化的同源和转基因小鼠，将在本提案中进一步检查。本次活动的具体目标建议是：具体目标 1：分析 B6Prdm16/D2 和 B6Prdm16/B6 小鼠的胸腺复旧情况。具体目标2：分析胸腺复旧延迟的机制。具体目标3：分析胸腺复旧延迟或加速的小鼠的免疫功能