Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis that predominantly afflicts children
and is the leading cause of acquired heart disease among children. Coronary artery aneurysms (CAA) develop
in 25% of untreated children with KD, leading to ischemic heart disease and myocardial infarction and to long -
term cardiovascular complications into adulthood. While high dose IVIG treatment plus aspirin reduces the
CAA from 25% down to 5%, up to 30% of KD patients are non-responsive to IVIG and have a higher risk of
developing CAA. Therefore, discovery of novel and more effective treatments to prevent the cardiovascular
complications (CAA) in KD is one of the highest research priorities.. A well-accepted mouse model of KD
vasculitis, CAA and myocarditis is available that closely mimics the immunopathologic features of the
cardiovascular lesions observed in KD patients. Recent genetic data, and data from experimental mouse
model of KD, have all converged on the critical role of IL-1¿ signaling in pathogenesis of the KD lesions.. Two
clinical trials using the IL-1R antagonist were recently initiated in KD patients who do not respond to IVIG.
However, emerging data suggests that inhibiting IL-1¿ with mAb or the IL-1R antagonist can significantly
increase the risk of infections (FDA database). Therefore, strategies to block the IL-1¿ pathway in more
proximal steps may be beneficial in KD and bypass the unwanted effect of increased risk of infection
associated with direct IL-1¿ antagonism. We obtained novel data to suggest that ER stress and mitochondrial
oxidative DNA damage may play a role in cardiovascular lesions of KD vasculitis. Several ER stress response
genes are significantly upregulated in whole blood cells of acute KD patients and in the LCWE-induced KD
vasculitis mouse model, implicating ER stress in KD pathogenesis. Therefore, the central hypothesis of this
exploratory R21 application is that ER stress is critical for robust NLRP3 inflammasome activation and IL-
1¿ release, which drives the cardiovascular pathology in KD. We propose interventions that can reduce
ER stress and prevent oxidative mitochondrial DNA damage, thereby preventing NLRP3 activation, mitigate
IL-1ß release and inflammation, and prevent KD lesions. To investigate these central hypotheses, we propose
the following Specific Aims: Aim 1: To define the role of ER stress and oxidative mitochondrial DNA stress in
the activation of NLRP3 inflammasome and IL-1¿ production that drives cardiovascular lesions associated with
KD vasculitis mouse model, and Aim 2: To determine the therapeutic efficacy of ER stress inhibitors and
inhibitors of mitochondrial ROS and oxidative mt DNA damage in the prevention of cardiovascular lesions of
KD vasculitis model. Modulation of these upstream pathways that stimulate activation of NLRP3 inflammasome
and IL-1¿ production may be attractive targets for new therapeutic agents to prevent the cardiovascular lesions
of KD without the increased risk for infections associated with direct IL-1¿ antagonism, using an experimental
model that has proven to be of translational value to humans.