Hematopoietic stem cells and longevity

造血干细胞与长寿

• 批准号: 8520129
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 37.19万
• 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/8520129
• 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

描述（由申请人提供）：本提案将重点研究胸腺退化的遗传变异的功能后果和潜在机制，胸腺退化是免疫衰老的标志之一。老年人接种疫苗失败至少是部分原因