Role of intracellular membrane signalosomes in B cell NF-kB activationThis proposal focuses on a novel mechanism that underlies NF-kB activation in peripheral B cell differentiationand, when dysregulated in autoreactive B cells, promotes pathogenic autoantibody responses in autoimmunediseases, such as lupus. As we contend, this mechanism is underpinned by the formation of intracellularmembrane signalosomes (IM signalosomes), e.g., as mediated by the interaction of signal adaptor TRAF6, anE3 ubiquitin ligase, with Rab7, an endosome-tethered small GTPase, in B cells upon CD40 engagement.

This application is for renewal of the T32 comprehensive institutional research-training grantCOSTAR (Craniofacial Oral-Biology Student Training in Academic Research). Building onlongstanding institutional research training experience, COSTAR has trained 26 DDS/PhDstudents, 41 PhD students, 26 Post-doctoral Fellows, 4 faculty fellows, and 147 summer dentalstudent research fellows since first funded in 2002.

Hypertension affects millions of people in the United States and worldwide. Improved understanding of themolecular and cellular origins of hypertension will improve the efficacy of treatment and diagnosis. TheEpithelial Na+ Channel, ENaC, is the final arbiter of Na+ excretion in the kidneys. As such, discretionary controlof ENaC fine-tunes renal excretion. Appropriate renal excretion is a key factor in the normal regulation ofarterial blood pressure. Consequently, dysfunction of ENaC and its upstream modulators cause dysregulationof blood pressure due to abnormal excretion.

This proposal combines a team with expertise in aging, tumor immunology, tumor immunotherapy, specificgenetically modified animal models and early phase clinical trials with a computational team having greatexpertise in analyzing and modeling aging of the immune system.

Despite the increasing numbers of aging individuals in our country, there is little understanding of theinteraction between the mechanisms of aging and the pathophysiology of age-related diseases. Research inthis area is essential since age is the largest risk factor for various diseases. If this relationship can be resolved,it would open new avenues for therapeutic interventions to treat/prevent age-related diseases. Oxidative stressis one of the fundamental biological processes that link aging and age-related diseases.