Thursday, April 25, 2024
4/25/2024
¿ DESCRIPTION (provided by applicant): The focus of this project is to investigate RIPK1 (RIP or RIP1), a novel player in autoimmune diseases, as revealed in recent studies by us and others. We hypothesize that RIP1 could be a mediator in a variety of autoimmune conditions through activation of a pro-survival/proliferation signaling. Therefore, targeting RIP1 could serve as an effective therapeutic approach. Gene mutations in Fas (Apo-1 or CD95) could lead to an autoimmune-lymphoproliferative (lpr) syndrome (ALPS) with certain characteristics of lupus. RIP1 was originally identified as a potential Fas-interacting protein. Subsequent studies indicate that RIP1 is also a component of the signaling complex of tumor necrosis factor receptor 1 (TNFR1). As a result, Fas-/-TNFR1-/- double mutant mice develop accelerated lpr diseases. However, the physiological function of RIP1 is poorly understood due to perinatal lethality in RIP1-deficient mice. Using a novel conditional mutant animal model, our preliminary data indicates that RIP1 plays a critical role in T cells. In our previous study, RIP1 deficiency was able to rescue embryonic lethality in mice lacking FADD, a mediator of apoptosis induced by Fas or TNFR1 through recruiting and activating the initiator caspase 8. This discovery marks a turning point in our understanding of programmed cell death (PCD), by revealing a potent necroptosis (programmed necrosis) pathway mediated in vivo by RIP1. However, it remains unclear why RIP1-/- mice and RIP1-/- FADD-/- double mutant mice display perinatal lethality. In contrast, embryonic and postnatal development was normal in animals lacking both FADD and RIP3. The latter is a homologue of RIP1 and exclusively signals necroptosis. Therefore, absence of FADD unleashes necrosis, which is dependent on RIP1 and/or RIP3. The resulting RIP1-/-FADD-/- double mutant mice develop ALPS/lpr, which are more severe than that in Fas mutant mice. Here, we hypothesize that targeting RIP1 would promote cell death and serves as a strategy for treating lpr-autoimmune disease. However, the regulatory mechanism of this novel function of RIP1 in the immune system is not well understood. Therefore, we propose: 1) to test for the effect of genetic and pharmacological ablation of RIP1 function on suppressing lpr-autoimmune diseases; 2) to elucidate the pro-survival pathway(s) in primary lymphocytes that is mediated by RIP1; 3) to identify the structural/functional domain/motif in the RIP1 protein through in vivo functional complementation study, to facilitate drug design. Successful completion of these specific aims will provide new insights into the mechanisms regulated by RIP1 and lead to better design of therapies for lymphoproliferative, autoimmune and related diseases.
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