The interconnected insulin-like growth factor (IGF), mammalian target of rapamycin (mTOR), and p53 signaling pathways play many important roles in cellular function, including regulation of cell growth and death, sensing of glucose and nutrient levels, and response to stress and DNA damage. Defects in the three pathways have been implicated in disease. Drs. Notterman and Levine believe the pathways may also act on the central nervous system to contribute to autism. Several genes in the three pathways — such as the PTEN and tuberous sclerosis genes — have already been implicated in autism. Mutations in PTEN have been found in individuals with autism, and experimental mice lacking the gene have defects in their central nervous system that lead to behavioral changes. The tuberous sclerosis genes have also been directly linked to autism. Given these preliminary findings, Notterman and Levine plan to look for links to autism in a set of 14 genes from the three pathways. The researchers propose to analyze variations in the genes' sequences to identify specific variations — and combinations of these variations in single and multiple genes — that occur more frequently in individuals with autism than in the general population. Once these autism-linked sequence variations are identified, the researchers plan to examine their effects at the molecular level, including whether they alter the resulting proteins' expression, function and interactions with other proteins. The researchers also plan to find any autism-linked variations in genes that are regulated by androgens or estrogens, or genes that are linked to the X or Y chromosomes, as these variants may help explain why autism occurs at a much higher rate in males.