Sunday, May 11, 2025
5/11/2025
Determining the Involvement of PERK in TMAO Induced Atherosclerosis - ABSTRACT: The World Health Organization reports cardiovascular disease (CVD) as the global leading cause of death. Our long-term goal is to improve public health by advancing clinical therapies and management of CVD. Trimethylamine N-oxide (TMAO) has emerged as a dietary derived metabolite highly predictive of atherosclerosis and CVD mortality. It is robustly elevated in humans with CVD across multiple independent studies, and its dietary supplementation causes atherosclerosis in animal models. But efforts to leverage the TMAO pathway therapeutically are met with skepticism, as a clear mechanism of TMAO action continues to be elusive. Therefore, defining the mechanism of TMAO-induced atherosclerosis is of fundamental importance to produce meaningful change in treatment options for those dying of CVD. Recently, our lab reported the first and only known receptor for TMAO; TMAO specifically binds and activates the stress signaling kinase PKR-like Endoplasmic Reticulum Kinase (PERK). However, two central questions are still unaddressed: 1) how does TMAO-activation of PERK drive disease, and 2) is PERK activity required for TMAO to cause atherosclerosis? This proposal presents a research strategy to answer the above questions. We report preliminary data that acute TMAO causes PERK phosphorylation (pPERK) in mouse aorta, and that chronic TMAO feeding increases aortic inflammation in a PERK dependent manner. We also show use of a PERK inhibitor prevents TMAO-induced increases of CVD risk factors, blood glucose and plasma cholesterol. Further, we confirm that TMAO activates pPERK, but also that it induces a unique conformational state distinct from classically described PERK activation by unfolded proteins. Thus, our central hypothesis is that TMAO drives atherosclerosis via a unique activation of the PERK axis. In Aim 1, we propose to define TMAO’s effects on the PERK signaling complex in the vasculature. In Aim 2, we will test the requirement of PERK in TMAO’s ability to cause atherosclerosis in ApoE-/- mice. The experiments described will identify a long-sought mechanism of how TMAO causes atherosclerosis, and they will investigate how activation of the stress response protein, PERK, induces cellular dysfunction. The proposed training plan covers training in molecular and physiologic tools to assess metabolic contributions to CVD, presentation, communication, and publication opportunities, and an overall roadmap for growing into a productive and collaborative independent investigator. Additionally, the institutional environment at both the Harvard T.H. Chan School of Public Health and Boston Children’s Hospital ensures robust access to abundant resources and equipment, core facilities, and brilliant minds that will continually support the growing needs of the project. We believe the enclosed aims will interrogate the role of PERK in mediating the well- described effect of TMAO-induced CVD, and they will open a flood gate of therapeutic options already lying-in wait to prevent premature cardiovascular deaths.
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