Molecular mechanisms that control the loss of T progenitor competence in aging

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Whether age-related defects occur in hematopoietic progenitors for T cells was previously not well understood. We recently assessed the ability of bone marrow progenitors from aged mice to contribute to the T cell lineage, and established that aging significantly impacts the T cell potential of hematopoietic progenitors. Defects in T cell development were clearly evident when aged hematopoietic stem cells (HSC) and downstream multipotent progenitors (MPP) were assessed in vivo, and also in vitro using cell co-culture with OP9 stromal cells engineered to express Notch ligands (OP9- DL1) that support T cell differentiation. In the current application, we propose to exploit the OP9-DL1 cell culture system to elucidate the molecular changes underlying the loss of T lineage potential in aged hematopoietic progenitors. We hypothesize that the age-associated loss of T lineage competence in aged stem and progenitor cells is caused by specific molecular changes in gene expression. We further hypothesize that restoration of expression of these molecules will restore T lineage potential to aged hematopoietic progenitors. We will identify molecules whose expression is altered in HSC and downstream MPP isolated from aged mice, as compared to HSC and MPP from young mice. Identification of such molecules will be initially performed using DNA microarray based interrogation of sort-purified progenitors. We will confirm altered expression of identified molecules by hematopoietic progenitors using real-time PCR, coupled with additional approaches when possible. We will use retroviral gene transduction of HSC and MPP to ask whether forced expression of molecules showing reduced expression in aged progenitors is sufficient to correct defective T cell development from aged HSC and MPP in the OP9- DL1 system. These studies should provide insight into molecular mechanisms underlying the age-associated loss of T progenitor competence. PUBLIC HEALTH RELEVANCE Whether age-related defects occur in hematopoietic progenitors for T cells was previously not well understood. We recently reassessed the ability of bone marrow progenitors from aged mice to contribute to the T cell lineage, and established that aging significantly impacts the T cell potential of hematopoietic progenitors. In the current application, we propose to investigate the molecular basis of the age-related defects in T progenitor potential that we have discovered. These experiments will allow a molecular characterization of age-related defects in T cell development, and may enable therapeutic enhancement of T lineage reconstitution in clinical settings such as aging and bone marrow transplantation.