[R01] The JNK2-NLRP3 nexus in atrial fibrillation and its anti-AF therapeutic potentials
Ente: National Institute on Alcohol Abuse and Alcoholism
Scadenza: 2029-04-30
Importo max: 591.477 EUR
Paese: US
Descrizione
Excessive binge alcohol intake is a well-recognized risk factor for atrial fibrillation (AF), the most common arrhythmia
with a high morbidity and mortality, yet current therapies have suboptimal effectiveness. [While aging is an
unavoidable AF risk factor, alcohol as a secondary stressor exacerbates AF risk in the aging population.] Clinical
data suggest that one-third of all new-onset AF cases are related to alcohol intoxication and alcohol abuse brings a
high AF risk even in people without co-existing cardiovascular diseases. It is a classic concept that enhanced
inflammation contributes to alcohol-caused organ damage, which could also lead to AF. However, the
ineffectiveness of the anti-inflammation therapies in AF patients has demonstrated the urgent need to understand
the detailed underlying mechanisms of inflammation-associated AF and explore novel anti-AF therapeutic
targets. The goal of this proposal is to fill this knowledge gap by establishing a previously unrecognized crosstalk
between the pro-inflammatory signaling pathways and the stress kinase JNK2 in AF pathogenesis. In human donor
atria, binge alcohol exposure increased pro-inflammatory TNFα and IL1β-NLRP3 signaling along with activated JNK2.
And TNFα or IL1β significantly enhanced diastolic SR Ca2+ leak and triggered activities (Ca2+ waves and delayed
after depolarizations), while either JNK2 or NLRP3 inhibition effectively alleviated those triggered activities,
suggesting a crosstalk between JNK2 and pro-inflammatory signaling. However, we found that only TNFα, but not
IL1β, activates cJNK2. Yet, TNFα is known to upregulate IL1β signaling, which could explain the involvement of
NLRP3 in TNFα-induced triggered activities. But why JNK2 is not influenced by IL1β yet is critically involved in
IL1β-NLRP3-mediated Ca2+ mishandling remains completely unknown. [This proposal is thus aimed to establish
a novel and potentially paradigm-shifting and translationally important link between the JNK2-NLRP3 nexus (as a
pathological nodal point; it has never been revealed before) and a complex web of co-existing pro-inflammatory
pathways in AF pathogenesis and most importantly, testing therapeutic potentials of targeting this pathological
nexus as a novel anti-AF approach.] Our multi-discipline team will use a unique diversified approach (molecular
biochemistry to single channel/myocytes/whole-heart electrophysiology in animal models/human donor hearts)
to systematically address two Specific Aims 1) Determine the underlying mechanisms of the JNK2-NLRP3
feedback loop in atrial Ca2+ mishandling; 2) Establish the functional contribution of JNK2 and/or pro-inflammatory
signaling pathways in binge alcohol-evoked arrhythmic activities and AF pathogenesis. The scientific premise of
this proposal is strong because it integrates important functional measurements and fundamental mechanistic studies
along with appropriate alternative approaches. [Cardiac specific interventions (in vivo atrial gene transfe
Istituzione: OHIO STATE UNIVERSITY
PI: Xun Ai
Progetto: 5R01AA031056-03
Settori: National Institute on Alcohol Abuse and Alcoholism
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.