For this program project, we will establish a bioinformatics core to process and analyze the large amount of data that will be generated by its four projects. We propose a comparative study of genome maintenance and its molecular and cellular end points in relation to human aging. While our work in the past has led to the conclusion that defects in genome maintenance systems have detrimental molecular, cellular and physiological effects that mimic normal aging, there is uncertainty about the most relevant pathways involved and their relative functional importance, especially for human aging. Lack of this information is an important problem, because, without this knowledge, acquiring the ability to modulate aging on the whole organism level is highly unlikely. Our long-term goal is to understand the mechanisms that determine longevity. The overall objective of the bioinformatics core is to provide computational support and service to the project investigators, i.e., work with each project to handle data generated therein and to integrate data from all projects to achieve the aims of the program project grant as a whole. The central hypothesis of this Program is that defects in genome maintenance result in deleterious molecular and cellular outcomes caused by unrepaired DNA damage, including genome instability, transcription stress, and cell fate changes, which in turn drive the pathogenesis of both cancer and aging. This hypothesis has been formulated on the basis of a large body of data produced in this PPG. The rationale for a dedicated bioinformatics core is that a consolidated facility is needed to manage the large amount of data on the whole genome level generated by each of four highly integrated projects of this program project. This bioinformatics core will be established to achieve three specific aims: 1) To develop a web portal to warehouse and share data generated by the four projects; 2) To facilitate projects by processing and analyzing the data that they generate; 3) To integrate project data at the systems level and identify a genetic network of genome maintenance in aging and longevity. The function of the bioinformatics core is significant, because it will be set up to meet the challenge posed by the high volume of data that need to be generated, examined at multiple levels by a variety of approaches, integrated to develop the models of lifespan control, and shared among project investigators and the scientific community as a whole.
The proposed bioinformatics core is relevant to public health because a web data portal and novel computational methods will be developed to tackle the genetic bases and molecular mechanisms of cellular aging related to DNA damage repair and its molecular and cellular end points. The web data portal will also be used to disseminate the data to the larger research community. The proposed research is directly relevant to the NIA mission in that it pertains to developing fundamental knowledge that will help reduce the burdens of human disabilities associated with advanced age.
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