Hematopoietic stem cells and longevity

造血干细胞与长寿

• 批准号: 8387394
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 40.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387394
• 关键词: Address; Adolescence; Adult; Affect; Age; Aging; Agonist; Alleles; Animals; Antigens; 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 Mouse; 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; bone; cytokine; immune function; improved; in vivo; novel; reproductive; response

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 (PPARg) and through this activity regulates signaling by the cytokine TGF-b2, 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 PUBLIC HEALTH RELEVANCE: The focus of this proposal is the study of the mechanism underlying the age-related involution of the thymus, the organ were T lymphocytes are produced, which are essential for immunity. Vaccine failure in the elderly has been attributed at least in part to thymic involution. Understanding the significance, functional consequences and underlying mechanisms of thymic involution is therefore of critical importance to human health.

描述(由申请人提供)：这项建议将集中在胸腺退化的遗传变异的功能后果和潜在机制，胸腺退化是免疫老化的标志之一。老年人的疫苗失败至少在一定程度上是由于 由于幼稚T细胞池的减少，导致老年人对新抗原的免疫反应能力下降，从而导致胸腺退化。然而，幼稚细胞产量的减少与先前存在的记忆细胞的扩张有关。因此，胸腺退化和伴随的原始T细胞产生的下降可能允许建立更大的记忆细胞库，能够或迅速对感染做出反应，从而为成年生殖年龄个体提供更好的免疫力。因此，了解胸腺退化的意义、功能后果和潜在机制对人类健康至关重要。为了确定胸腺退化的机制，并建立胸腺退化延迟或加速的模型，我们利用近交系小鼠之间的遗传变异。我们已发表的和初步的数据表明，一个新的造血调节轴，由Prdm16组成，它增强了配体诱导的PPARg的活性，并通过这一活性调节细胞因子TGF-b2的信号转导，影响胸腺退化。Prdm16基因上的小鼠依赖于菌株的编码变异调节了这一机制的活性。为了明确这个位点在体内的作用，我们产生了Pdm16的DBA/2等位基因被敲入C57BL/6背景的小鼠(B6Prdm16/D2小鼠)。在对照组小鼠中，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+/-小鼠和胸腺退化延迟或加速的同源和转基因小鼠，将在这项建议中进一步研究。这样做的具体目的是 具体目标1：分析B6Prdm16/D2和B6Prdm16/B6小鼠胸腺退化情况。具体目的2：分析胸腺退缩延迟的机制。具体目标3：分析胸腺退化延迟或加速小鼠的免疫功能 公共卫生相关性：这项建议的重点是研究与年龄相关的胸腺退化的潜在机制，胸腺是产生T淋巴细胞的器官，而T淋巴细胞是免疫所必需的。老年人的疫苗失败至少部分归因于胸腺退化。因此，了解胸腺退化的意义、功能后果和潜在机制对人类健康至关重要。