Browsing by Subject "p63"
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Item Aging of the Thymic Epithelial Progenitor Pool is Determined by the p63-FoxN1 Regulatory Axis(2015-05-01) Burnley, Preston I.; Dong-Ming SuThe immune system is composed of various effector cells and molecules that must work in concert in order to protect the body against infections, auto-reaction, and tumor occurrence. These responses can be divided into two categories – innate and adaptive immunity. The innate response is the host’s first line of defense towards a pathogen by providing a physical and chemical barrier against infection. Once activated, innate cells such as macrophages and dendritic cells can engulf the bacterium, degrade it, and secrete proteins to destroy the pathogen. Although this response occurs immediately after an encounter with a pathogen, the innate immunity is neither long-lasting nor specific. In contrast, the adaptive immune response is initiated when the innate immune response is unsuccessful in eliminating the infection, allowing for recognition and response tailored for a particular pathogen. The cells that make up the adaptive response all originate from a common lymphoid progenitor found in the bone marrow. From this precursor arise natural killer (NK) cells (part of the innate response) and T and B lymphocytes. The T lymphocytes originate from the bone marrow but undergo development in the thymus, hence the name T cells. B lymphocytes, on the other hand, originate and develop in the bone marrow. With the exception of NK cells, these adaptive immune cells require antigen presentation in order to become activated. Once the T and B cells have matured and become activated they can work together to clear the infection by secreting cytokines and antibodies. The most important aspect of the adaptive immune response is its ability to produce immunological memory. Memory T and B cells are able to ensure a rapid and effective response to a second encounter, providing long-last immunity. Unfortunately, this well-ordered process, specifically the development of T cells, becomes compromised during aging. This is due to the fact that thymic involution (or shrinking of the thymus) occurs at the onset of puberty and continues throughout the lifespan, which is primarily resulted from age-related defect in thymic epithelial cells (TECs). The thymus is crucial for the generation of T cells so any compromise to the organ results in changes in the T cells, which can possibly lead to immune insufficiency and autoimmunity [1]. Additionally, these conditions are exacerbated with age [2, 3]. This research project will focus on the molecular mechanism(s) responsible for thymic involution. To do so, we focused on TECS and two genes associated with the homeostatic maintenance of the thymic microenvironment, p63 and FoxN1. These genes regulate the proliferation and differentiation, respectively, of thymic epithelial cells (TECs), thereby maintaining a properly functioning thymus. For this study we will utilize our mouse model (FoxN1 conditional knockout, FC) extensively because it mimics an aged thymus. This model allows us to study the thymic microenvironment of a mouse with a defect in the FoxN1 gene.Item AGING OF THYMIC EPITHELIAL PROGENITOR POOL IS DETERMINED BY THE P63-FOXN1 REGULATORY AXI(2014-03) Burnley, Preston I.; Su, Dong MingThe thymus is a vital organ necessary to fight infections. Unfortunately, it shrinks with age resulting in a compromised function. Our lab uses mice to study the events leading to the shrinkage, hoping to one day develop therapeutic agents to reverse the compromised function. Purpose (a): The postnatal thymic epithelial progenitor (TEP) pool is proposed to be regulated by the p63 and FoxN1 genes through proliferation and differentiation, respectively. However, the combined role of these two genes in the aging TEP is still a mystery. Evidence from murine models has elucidated contrasting roles of the p63 isoforms during the aging process. Methods (b): Wild type and FoxN1 cKO mice were used throughout the experiment to evaluate the amount of p21, p63, and FoxN1 present. Immunofluorescence and senescence staining was performed on frozen sections harvested from euthanized mice. PEI intrathymic injections were performed with either TAp63 or FoxN1 cDNA. Results (c): We found that TAp63+, but not ΔNp63+, thymic epithelial cells (TECs) were increased with age, accompanied with increased senescence associated β-gal clusters and p21+ TECs. Senescent clusters also developed after intrathymic infusion of exogenous TAp63 cDNA into young wild-type mice. Using our conditional FoxN1 gene knockout mouse model to disrupt TEP differentiation accelerated this senescent phenotype to early middle age. However, upon infusion of exogenous FoxN1 cDNA into aged wild-type mice resulted in only an increase in ΔNp63+ TECs, but no change in TAp63+ TECs in the partially rejuvenated aged thymus. Interestingly, using a novel FoxN1 transgenic mouse model to enhance TEP differentiation, ΔNp63+ TECs were decreased in young thymus. Additionally, the TAp63+ population contained a high percentage of phosphorylated-p53 and apoptotic TECs, but showed no changes in BrdU-labeled proliferation. Conclusions (d): FoxN1 controlled TEC differentiation as a bottleneck to determine TEP pool via affecting TAp63 and DNp63 levels. Thus, TEC homeostasis during aging has been determined through the p63-FoxN1 regulatory axis.Item ROLE OF THE P63-FOXN1 REGULATORY AXIS IN THYMIC EPITHELIAL CELL HOMEOSTASIS DURING AGING(2013-04-12) Burnley, Preston I.Purpose: Current knowledge about regulating proliferation and differentiation of thymic epithelial cells (TECs) by the genes p63 and FoxN1, respectively, in the prenatal thymus has led our lab to determine whether these genes also regulate TEC homeostasis during aging in the postnatal thymus. Methods: We used murine models to verify the role of a p63-FoxN1 regulatory axis in TEC homeostasis during thymic aging. Results: Our studies show that a proportion of pan-p63+ TECs was increased with age, among which the isoform, TAp63, as oppose to ΔNp63, was increased and accompanied by increased senescent cell clusters with age. Furthermore, in the postnatal thymus blockade of the TEC differentiation via a conditional FoxN1 knockout demonstrated an increase in TAp63 and senescent cell clusters as well. This proportion of TAp63+ TECs, however, was decreased when FoxN1 cDNA was exogenously administered into the aged thymus intrathymically. In addition, we found that increased TAp63+ populations contained high proportions of phosphorylated-p53+ and apoptotic TECs but showed no changes in BrdU-labeled proliferation. Lastly, TAp63 cDNA intrathymically injected into the young thymus showed an increase in senescent cell clusters but little change in FoxN1. Conclusions: We conclude that the expression of TAp63 has a reverse correlation with expression of FoxN1. During the natural thymic aging, decrease in FoxN1 causes an accumulation of undifferentiated TECs. This most likely leads to an increase in TAp63, thus resulting in an increase in cellular senescence and exhaustion of epithelial stem cells. This finally will cause age-related thymic involution and deteriorate thymic function.