The laboratory of Heidi J. Scrable, Ph.D., studies the tumor suppressor p53. Mutations in p53 are the most common genetic changes found in cancer.
Dr. Scrable and her colleagues uncovered a link between cancer and aging using a line of genetically engineered mice with altered p53 activity. These mice are not tumor prone like other p53 mutant mice, but they go through the aging process early and die at a younger than normal age.
By trying to understand the mechanism underlying these changes, Dr. Scrable and her team have learned that p53, in addition to preventing the proliferation of tumor cells, supervises the proliferation of normal cells, specifically stem cells, in response to adverse environmental events.
Inappropriate activation of p53 can disrupt this response and impair the (re)generative capacity of both embryonic and adult stem cells, which is necessary for normal development and healthy life span.
Research in Dr. Scrable's lab is centered on three topics and driven by questions such as:
- Aging. Aging can be defined as the loss of the ability of the organism to maintain homeostasis. How is the ability of p53 to suppress the proliferation of tumor cells related to its role in monitoring the production of normal cells for tissue regeneration and repair?
- Stem cells. Stem cells are cells that enable the generation and regeneration of the organism. How does p53 help stem cells adapt to changes in the environment, and what are the immediate and long-term consequences of these adaptations?
- Insulin/IGF pathway. This is a central axis regulating growth and longevity. Can we identify factors with the ability to protect or rejuvenate adult stem cells, with the aim of decelerating the loss of tissue function that accompanies aging?
Significance to patient care
Dr. Scrable's laboratory does basic research with strong translational potential. Efforts to identify interventions that can repair or replace mutant p53 genes as an anti-cancer therapy are ongoing, yet significant problems in implementing these therapies are anticipated.
One deleterious consequence of increased p53 function that Dr. Scrable's lab has identified is accelerated aging. The lab uses experimental models in mice to try and understand why and how increased p53 activity impairs stem cell function and tissue regeneration.
It is only by studying the consequences of deregulating p53 in the context of a complex, mammalian organism similar to humans that Dr. Scrable and her colleagues will be able to find appropriate intervention strategies that maintain the balance between tumor suppression on the one hand and stem cell utilization for healthy aging on the other.