The overall goal of our research is to achieve a greater understanding of the molecular basis of brain aging and how normal aging transitions to pathological aging, giving rise to neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The ongoing projects fall into 2 major areas: 1) The role of DNA damage and altered transcription in the aging process, and in particular the aging of the brain; and 2. Genes that cause Alzheimer's and Parkinson's disease.

Our laboratory investigates the aging human brain by defining transcriptional changes and sites of DNA damage on a genome-wide scale, and by modeling aspects of these processes in cultured cells and mice. Four related studies are ongoing: 1. We have developed a method for generating genomic maps that locate sites of DNA damage across entire chromosomes. By generating these maps, we can then ask: Is there a relationship between sites of DNA damage and changes in the expression of specific genes during aging? And does this relationship change in the genomes of individuals with cognitive decline, both at early stages and at the more severe stage we call Alzheimer's disease? By analyzing genomes of individuals who had rigorous cognitive function testing, we hope to achieve a greater understanding of age-related cognitive decline. 2. Why are some individuals able to live past 100 and remain cognitively intact? The molecular basis of extreme longevity in the human population is poorly understood. To address this intriguing issue, we have taken a systems biology approach by generating transcriptional profiles and DNA damage maps from individuals who lived to be greater than 100 years of age. 3. Can we model human aging in mice? To begin to address this question, we are studying gene knockout mouse models with genomic instability to determine whether they recapitulate aspects of normal brain aging. 4. Only aging humans develop the pathology of Alzheimer's disease, raising the question of what is unique about the aging human brain. To obtain greater insight into this question, we have defined the aging transcriptome at a genome-wide level from mouse to man. This database is a fertile starting point for investigating the molecular evolution of human-specific neurodegenerative diseases.

A complementary area of interest relates to genes that cause Alzheimer's and Parkinson's disease, and how understanding the relevant molecular mechanisms may confer insight into normal versus pathological aging. Ongoing studies are focused on signal transduction and repair mechanisms that cause disease when compromised.

The studies in this laboratory frequently involve interdisciplinary approaches with collaborations between molecular and computational biologists, both within the lab and with other labs. The approaches range from molecular and cell biological studies in vitro to the analysis of genetically engineered mice and the human brain.