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Improving Thymus Function by RB Inactivation

Lucile Packard Children’s Hospital at Stanford University School of Medicine
Julien Sage, PhD
Grant Type: 
Springboard Grants
Year Awarded: 
Type of Childhood Cancer: 
General Pediatric Cancer, Leukemia, Retinoblastoma
Project Description: 

Children with cancer face many health challenges before, during, and after treatment. In particular, one major side effect of most chemotherapeutic approaches as well as bone marrow transplantation strategies is depletion in immune cells. This decrease in immune function may increase the risk of opportunistic infections as well as cancer relapse.

T lymphocytes are a major component of the immune system; T cells are produced by the thymus. The thymus undergoes early degeneration in normal healthy individuals (termed involution) slowly diminishing the capacity to mount effective immune responses to new stimuli. In cancer patients, a transient loss of immune cells and the stress related to treatment have been shown to accentuate thymic involution. Strategies to limit thymic involution and promote thymic function are critically needed in cancer patients.

We propose here to investigate the mechanisms of thymic involution to identify novel means to control thymic output in pediatric cancer patients. Based on our preliminary analysis, we hypothesize that the members of the retinoblasotma protein (RB) family, which are central regulators of cell cycle control and differentiation, normally participate in the process of thymic involution by restricting the expression of the Foxn1 transcription factor. We propose that transient inactivation of RB family function may counteract thymic involution. To test these ideas, we will use a combination of mouse genetics, histopathological analysis, and immunological assays.

These experiments will provide new insights into the mechanisms of thymus involution and may identify novel means to control thymic function to improve the health of children with cancer.