2021-01-062024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/652671"個體自初次細胞分裂，細胞便不可避免的逐漸失去功能而老化。老化形成有九大原因：基因不穩定、端粒縮短、表觀遺傳變化、蛋白質恆定喪失、營養感應失調、粒線體異常、細胞衰老、幹細胞過度耗損、以及細胞間訊息傳遞改變。然而目前對調控老化的詳細分子機制仍尚未明瞭。 卡路里限制可以延長壽命，而磷酸化調控許多訊息傳遞，為了瞭解老化詳細的機制，我們用酵母菌建立了卡路里限制下磷酸化調控的蛋白資料庫。利用質譜儀，我們發現約800個蛋白受到卡路里限制而改變磷酸化。其中我們只發現一個關鍵的動作：PKA磷酸化Ids2調控營養感應、蛋白質恆定及老化現象 (Chen et al., 2019, eLIFE)。推測Ids2可能作為peptidyl prolyl isomerase來參與粒線體功能調控的佐監護蛋白，然而Ids2的受質及其調控機制細節尚需進一步瞭解。 欲知Ids2如何調控細胞功能，我們將尋找它的受質、受質辨識的方式、及受質如何提升粒線體功能並延長壽命。由於Ids2自酵母菌到人類 (FKBP4)在演化上被高度保留，在後續的研究，我們將探索PKA調控的Ids2磷酸化的現象，是否亦存在於更高等的真核生物體系統。 未來3年，我們規劃致力於下列目標： 1. 尋找Ids2幫助折疊的受質。 2. 了解Ids2結合/辨識其受質的過程。 3. 探討與Ids2發生作用的受質是否對粒線體的功能有所影響。 4. 在更高等的物種，這調控現象是否在演化中被保留下來。 此計畫旨在瞭解細胞壽命延長的分子機制，亦針對維繫粒線體功能提供知識與藥物治療方式。蛋白質的恆定對於神經的健全極為重要，甚至能影響大腦功能。這些關鍵的發現將能左右諸多神經性退化疾病的治療。" "Aging is an unavoidable process which cells gradually lose fitness from their first cell division. Nine hallmarks are generally considered to contribute to the aging process and together determine the aging phenotype: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, detail mechanisms linking these hallmarks are still enigmatic and waiting for exploration. To understand the detail mechanisms of aging process, we previously identified phosphorylation sites globally under calorie restriction in yeast using phosphor-column purification and LC/MS-MS analysis. Among ~800 calorie restriction-driven phosphorylation alterations, we only found one event that controls nutrient sensing, proteostasis, and aging: PKA-mediated Ids2 phosphorylation (Chen et al., 2018, eLIFE). Ids2 is a co-chaperone which may serve as a peptidyl prolyl isomerase to regulate mitochondrial function. Nevertheless, the substrates/clients of Ids2 and its mediated mechanisms have not been identified. To determine how Ids2 control aging and mitochondrial function, we will identify its substrates/clients, understand how Ids2 recognizes its substrates/clients, and how the functions of these substrates/clients influence mitochondria and lifespan. Since Ids2 is conserved from yeast (Ids2) to human (FKBP4), we will see whether these findings are conserved among higher eukaryotes. In the next 3 years, we plan to focus on the following aims: 1. What are the folding substrates/clients of Ids2? 2. How Ids2 recognizes/recruits substrates/clients. 3. How the substrates/clients of Ids2 control mitochondrial function. 4. Are these mitochondrial regulations conserved in higher eukaryotes? This project will also advance our knowledge on molecular mechanisms of calorie restriction-driven longevity, and offer conceptual and therapeutic approaches for mitochondrial function. Since neuronal protein homeostasis is vital for neuronal maintenance hence affects proper function of the brain, the findings here will be critical for treatment of many neurodegenerative diseases."老化粒線體蛋白質折疊蛋白質恆定Ids2/FKBP4AgingMitochondriaProtein FoldingProteostasis