RESUMEN
Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.
RESUMEN
BACKGROUND: Combining clinical and research excellence has become an increasingly difficult endeavor for thoracic surgeons, with typical success rates for the National Heart, Lung and Blood Institute and the National Cancer Institute being 25.1% and 11.3%, respectively. The Thoracic Surgery Foundation (TSF), which is an arm of The Society of Thoracic Surgeons, provides research awards and grants aimed at early career faculty to assist in securing federal peer-reviewed funding. The aim of this study was to assess the impact of these awards. METHODS: Faculty awardees of the TSF research awards from 1995 to 2019 were included in the study. The scholarly work of awardees was assessed by using Scopus , MEDLINE, and Google Scholar for publications, citations, and h-index. The National Institutes of Health (NIH) RePorter and the Federal RePorter were used to search for any grants awarded to these individuals. For publications and citations associated with a TSF grant, a 4-year window from the time of the research award was used. RESULTS: Fifty-two research awards were given to early career faculty during this study period, and 8 (15%) were awarded to MD PhDs. Six (12%) of awardees were female. Cardiac faculty members were awarded 27 (52%) awards, and general thoracic faculty members were awarded 25 (48%); of the cardiac faculty, 4 (17.4%) were congenital cardiac faculty. In the 4-year period after the TSF grant award, the mean number of published articles per awardee was 23 (interquartile range [IQR], 12 to 36), with a median citation count of 147 (IQR, 32 to 327). The current median h-index was 26 (IQR, 15 to 36), with 2323 (IQR, 1173 to 4568) median citations. Forty-eight percent of all awardees received at least 1 subsequent grant; 40.4% of these awardees received grants from the NIH, and 25% had 2 or more NIH grants. Comparing academic position at the time of the award with current position, 54% of awardees had an advancement in their professional rank. On analyzing leadership positions, 42% of awardees were division chiefs, 21% were associate clinical directors, and 28% were clinical directors. CONCLUSIONS: Being a recipient of the TSF award may position an individual to excel in academic medicine, with a large portion of awardees improving their academic standing with time. The rate of successful NIH grant funding after being a TSF awardee is higher than typical institutional success rates.