Role of neuroendocrine stress response in inflammatory a

National Institute Of Mental Health

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Abstract

The research of the Section on Neuroendocrine Immunology and Behavior focuses on several aspects of central nervous system - immune system interactions in animals and humans. These studies aim at defining the underlying mechanisms of hypothalamic-pituitary-adrenal (HPA) axis - immune system interactions pathophysiological relevance of these interactions to susceptibility and resistance to autoimmune inflammatory diseases and behavioral responses to stress. Project 1. "Genetic linkage and segregation studies in inbred rat strains", focused on identifying the genetic basis for co-inherited traits of inflammatory disease susceptibility, HPA axis dysregulation and patterns of behavioral responses to stress in inbred rat strains, using genetic linkage and segregation. These genetic linkage and segregation studies have been completed and indicate in an F2 intercross of inflammatory susceptible and resistant rat strains, that two regions, one on chromosome 10 and one on chromosome 2, link with innate (carrageenan-induced) inflammation, a sub-phenotype of more complex autoimmune inflammatory disease. The chromosome 10 linkage region (syntenic with a region on human chromosome 17 that links to a variety of autoimmune inflammatory diseases) contains several candidate genes, including the CRH receptor type 1 and ACE, that play a role in HPA axis regulation. There is no mutation in the coding region of CRH-R1 and the point mutation in ACE does not play a role in the inflammatory trait. The genetic linkage and segregation phase of these studies has been terminated and current studies focus on identifying candidate genes of interest through the use of expression microarrays. Results from these two approaches will be merged to identify genes of interest for further study. Preliminary studies indicate several potential candidate genes of interest that are being validated by RT-PCR, in situ hybridization and immunohistochemistry of appropriate tissues. These findings have immediate relevance to risk factors for susceptibility and resistance to conditions including septic shock. In addition to shedding light on potential candidate genes of interest, the genetic linkage and segregation studies indicated that genetic factors contributed to only 35% of variance of the QTL. Current studies therefore also focus on identifying early developmental factors contributing to the environmental variability of the HPA axis and inflammatory traits. These studies indicate that maternal behavior, gender and genetic factors interact to contribute to the adult set-point of the HPA axis response in these strains.