[R01] Deciphering the role of GFPT2 in radiation-induced cardiovascular disease
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-05-31
Importo max: 717.760 EUR
Paese: US
Descrizione
Project Summary/Abstract
Radiation-induced heart disease affects 15-30% of cancer patients who undergo radiation therapy (RT) to the chest
and encompasses a broad range of cardiovascular disease (CVD) with potentially profound prognostic implications.
Despite its impact, the exact causes of RICVD remain uncertain, and limited preventive treatments are available.
Addressing this gap is an urgent requirement. Ionizing radiation (IR) has been shown to promote a persistent
senescence-associated secretory phenotype (SASP) in myeloid cells, which plays a key role in the development of
CVD. IR-induced SASP and accumulating senescent myeloid cells in tissues can trigger prolonged inflammation, but
the mechanisms by which IR induces SASP remain unclear. Our long-term goals are to determine the fundamental
mechanisms contributing to RICVD, identify patients at high risk for RICVD, and establish novel therapeutic
approaches. It has become evident that glutamate metabolism plays a key role in promoting the survival of senescent
cells and SASP induction. We conducted a metabolite profiling and found that both glutamate (Glu) and amino sugar
metabolisms were upregulated in human monocyte-derived macrophages from patients with RICVD compared to
those from non-RICVD patients. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) is a crucial enzyme that
upregulates both glutamate and amino sugar (a precursor of glycosaminoglycan (GAGs)); our preliminary data
showed that GFPT2 is acetylated at K17 and K254, which stabilizes GFPT2 expression after IR, and that this
acetylation is regulated by NAD+-dependent sirtuin 6 ( SIRT6) deactivation. We hypothesize that IR-induced telomeric
DNA damage initiates a positive feedback loop in which PARP activation leads to TOP2 degradation via TOP2-
PARylation. The sustained TOP2 reduction stabilizes GFPT2 by deactivating SIRT6 and upregulating acetylation,
promoting Glu/amino sugar/GAGs, SASP, and thus RICVD. We will test our hypothesis by pursuing the following
three specific aims: In Aim 1, we will Investigate the role of the PARP-TOP2β positive feedback loop in provoking Glu
and GAGs and subsequent SASP after IR in vitro. In Aim 2, we will determine how SIRT6 deactivation-mediated
GFPT2 acetylation/stabilization and subsequent Glu/GAGs contribute to the persistent induction of SASP following IR
in vitro . In Aim 3, we will determine the role of PARP1-TOP2β and Glu/GAGs in IR-induced atherosclerosis and atrial
fibrillation (AF) in an in vivo setting. By elucidating the role of the PARP-TOP2β axis and NAD+-dependent GFPT2
acetylation/stabilization and its subsequent impact on Glu metabolism and SASP induction, this study a/GAGsims to
enhance our understanding of the mechanisms underlying the persistent induction of SASP after radiation in myeloid
cells. Additionally, the investigation of GFPT2 activation and Glu/amino sugar/GAG’s regulatory role may provide
insights into therapeutic strategies for mitigating RICVD.
Istituzione: UNIVERSITY OF TX MD ANDERSON CAN CTR
PI: Jun-Ichi Abe, Guangyu Wang
Progetto: 5R01HL179815-02
Settori: National Heart Lung and Blood Institute
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