Mailing Address: Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 84-171, Berkeley, CA 94720
Email Address: Jcampisi@lbl.gov
Dr. Campisi's laboratory aims to understand the molecular and cellular basis of aging in animals. Through the study of human and mouse cells in culture and of the organism Caenorhabditis elegans, she explores the relationship between tumor suppression mechanisms and aging. Her laboratory also studies the role of telomeres and telomere binding proteins in regulating gene expression and genomic stability, and the mechanisms by which defects in DNA repair pathways cause premature aging and cancer.
Cellular senescence is the essentially irreversible growth arrest that occurs when cells experience damage or other stimuli that puts them at risk for neoplastic transformation. Although cellular senescence is a potent tumor suppressive mechanism, increasing evidence from the Campisi lab suggests that senescent cells can contribute to aging and age-related diseases, including the development of late life cancers. This is because the senescence response causes widespread changes in gene expression, some of which deregulate cellular functions. Thus, cellular senescence may be an example of evolutionary antagonistic pleiotropy, benefiting young organisms by protecting them from cancer but compromising old organisms by the accumulation of dysfunctional senescent cells. Among the questions the Campisi lab aims to answer are: What causes the growth arrest and dysfunctional phenotypes associated cellular senescence? How do senescent cells alter the tissue microenvironment and what is the impact of these alterations on the proliferation and differentiation of neighboring cells? How do the tumor suppressor proteins RB and p53 regulate the establishment and maintenance of the senescent phenotype? And how do cells decide whether to undergo cellular senescence or apoptosis (programmed cell death) in response to damage, and how does this decision impact the aging and cancer susceptibility of organisms?
A number of DNA repair proteins have now been identified that appear to be important for preventing cancer, aging or both. For example, the helicases defective in the Werner syndrome results in premature aging and increased cancer, the Bloom syndrome results in increased cancer without premature aging, and trichothiodystrophy results in premature aging without elevated cancer. In collaboration with laboratories at the Lawrence Berkeley National Lab, University of Texas (San Antonio) and Erasmus University (Netherlands), the Campisi lab is studying the biochemical and cellular properties of these proteins in order to understand how they maintain genomic stability and suppress aging and cancer. Along the same lines, telomeres are structures that cap the ends of chromosomes and prevent them from degradation or fusion by the cellular DNA repair machinery. Functional telomeres are necessary in order to prevent cellular senescence and genomic instability, and hence aging and cancer. In addition, some telomere-associated proteins may also regulate heterochromatin, and thus gene expression. The Campisi lab aims to understand the nature of the telomeric structure, and how telomere-associated proteins may organize the nucleus and regulate heterochromatin domains.
An important question in aging research is, "What are the molecular and cellular bases for the large differences in life span among species?" A major source of DNA damage is reactive oxygen species, which derive in large measure from endogenous mitochondrial metabolism. Recent findings from the Campisi lab suggest that differences in sensitivity to oxidative stress may underlie some of the differences in longevity and cancer susceptibility between mice and humans. Stress resistance is a common correlate of longevity, and thus understanding the mechanisms by which organisms develop stress resistance is important for understanding why organisms age. It has long been appreciated that low levels of environmental stress often confer resistance to a higher level of stress, a process termed hormesis. In collaboration with laboratories at the Lawrence Berkeley National Lab and Buck Institute, the Campisi lab is studying the mechanisms of radiation-induced hormesis in nematodes, mouse cells and human cells. An additional factor that may explain species-specific differences in aging and age-related disease is the structure and function of checkpoint and tumor suppressor proteins such as p53, which, in collaboration with a laboratory at the Buck Institute, is being studied in nematodes, mouse cells and human cells.