研究主題 (Research)
細胞壓力的增加是老化最主要的現象之一，而造成這個現象的原因是細胞抗壓的能力會隨著年紀增長而衰退．我們實驗室主要的研究課題就是要暸解細胞抗壓反應是如何被控制的．這是一個在生物學上相當有意思的課題，因為細胞抗壓反應強度的高低可以決定動物的壽命長短．此外，在醫學上細胞抗壓反應也和許多老化的退化性疾病相關．在實驗室裡，我們用斑馬魚來探討各種生理反應對細胞抗壓能力的影響．我們主要聚焦在熱休克反應 (heat shock response)與粒線體壓力反應 (mitochondrial UPR)．我們也會用斑馬魚建立老化相關的退化疾病模式，來研究細胞抗壓反應在其中扮演的角色．
As we age, our cells tend to accumulate more and more damages in DNA, proteins and other bio-molecules. Our cells have evolved a set of abilities to fix the damages. These abilities are the “cellular stresses responses” because of their role in mitigating cellular homeostatic imbalance, i.e., stress. When in decline, the cellular stress responses are responsible for causing aging; on the other hand, when hyper-activated, they are able to extend lifespan. We are interested in understanding how the cellular stress responses, including the heat shock response and the mitochondrial UPR, are regulated. Particularly, we would like to investigate how physiology intersects with the cellular stress responses. Our main strategy is to use a vertebrate model organism, zebrafish, to explore how various veterbrate physiological processes, which are highly similar between zebrafish and human, play a role in orchestrating cellular stress responses at the systemic level, and furthermore, to gain understanding of age-related diseases from this perspective.
研究方向1: 逆轉老化 (Project 1: Cellular rejuvenation during tissue regeneration)
斑馬魚擁有強大的組織再生能力，也因此是研究組織再生的重要模式動物。我們之前的研究發現，粒線體壓力反應在斑馬魚魚鰭再生中會被活化。由於粒線體壓力反應的活化會帶來延長壽命的效果，我們猜測新的再生的魚鰭組織年紀會被回復到較年輕的狀態。而我們初步的研究顯示確實如此。我們接下來的目標是要找出年紀回復的機制，然後要將此機制套用在其他動物上，去實現逆轉老化的終極目標。
Our previous study has shown that one of the mitochondrial stress responses, the Sirt1-UPRmt, is essential for the fin regeneration in zebrafish. The Sirt1-UPRmt signaling is best known for its role in lifespan regulation, in which activating this signaling extends lifespan in several animal species. Hence, we hypothesize that during fin regeneration not only a new functional tissue is form, but the new tissue is also younger. We are testing this idea by examining the cellular stress response activities in the newly regenerated tissue. Our ultimate goal is to implement this cell rejuvenation process to restore the cellular stress responses and the age in old animals.
研究方向2: 細胞韌性 (Project 2: Stress hormesis)
在對抗暫時性的壓力後，細胞往往會產生一些持久的變化。這些變化能使細胞在下一次經歷相同或更強壓力時能有更強的韌性(hormesis)，進而增加存活率。目前細胞韌性的機制大致上被認為是細胞內部的變化所造成。然而在細胞外或是生理層面上的因子是否在抗壓韌性中扮演角色，現在還完全不暸解。我們利用斑馬魚來探索不同的生理反應對細胞產生抗壓韌性的影響。
“What does not kill, makes you stronger.” It is not just a song lyric. It is a conserved feature of cellular stress responses. A mild, non-lethal, stress can generate long lasting stress response activity that ensures survival during subsequent, and perhaps stronger, stressful conditions, and ultimately extends the animal’s lifespan (This is called hormesis.). We believe that in addition to cell intrinsic properties, physiological processes could be part of the bases for hormesis. We have found that zebrafish also experiences hormesis in heat shock stress. Therefore, we use this model to explore the physiological aspect of stress hormesis mechanisms.
研究方向3: 老化疾病: 肌少症 (Project 3: Age-related disease: Sarcopenia)
肌肉流失是老化的過程中最常見的退化現象。肌纖維蛋白減少的原因部分是由於肌細胞累積過多細胞壓力所造成。為了研究細胞抗壓反應對肌肉維持纖維蛋白的影響，我們建立了斑馬魚肌少症的模式．我們發現粒線體抗壓反應會在病變的斑馬魚肌肉細胞中被活化。這代表粒線體的健康對肌肉維持纖維蛋白有相當緊密的關係。我們目前要探討這其中可能的機制。
Loss in muscle mass is one of the most common age-related physiological decline. The reduction in myofibril content can be attributed to failed cellular stress responses to maintain protein quality in muscle cells. We use larval zebrafish to model loss of skeletal muscles and find that the mitochondrial stress response is activated in the defective muscles. Therefore, we will investigate the role of mitochondrial dysfunction and mitochondrial stress responses in muscle mass maintenance. Our goal is to reveal what causes mitochondrial dysfunction in sarcopenic muscles and, more importantly, finding ways to restore mitochondrial quality and stop the loss of muscle mass during aging.
大學生： 研究生：
陳慶 (生科系) 林振宇 (預研)
辛晨 (學士班) 張友綸 (生技所碩一)
洪妙汶 (醫科系)
歡迎有興趣的大學及研究所同學加入我們的團隊。
We look forward to having you as part of our team!
成員 (Who We Are)
林亦凡(Yi-Fan Lin)
Email: yflin@life.nthu.edu.tw
B.S., National Taiwan University,
Department of Zoology
M.S., National Taiwan University,
Institute of Molecular Medicine
Ph.D., New York University,
Department of Genetics and
Developmental Biology
11.2020
歡迎兩位大二生加團隊
1.2021
成功建立第一個 DNA construct
10.2021
The first Lin lab paper has been accepted in iScience. 🎉🎉🎉
06.2023
生科系大三陳慶獲得國科會大專生研究計畫助！
🎉🎉🎉
03.2021
CSA Lab
首條螢光魚誕生
請追蹤我們的IG帳戶，暸解實驗室最新消息．
Please follow us on Instagram to check out what we are up to recently.
動態 (News and Activities)
Selected Publications
1. Lin YF*, Sam J, Evans T. (2021) “Sirt1 promotes tissue regeneration in zebrafish through
regulating the mitochondrial unfolded protein response.” iScience, 24(10):103118
(*Corresponding author)
2. Fiorese CJ, Schulz AM, Lin YF, Rosin N, Pellegrino MW, Haynes CM. (2016). “The transcription
factor ATF5 mediates a mammalian mitochondrial UPR.” Curr. Biol. 26(15):2037-43
3. Lin YF, Schulz AM, Pellegrino MW, Lu Y, Shaham S, Haynes CM. (2016). “Maintenance and
propagation of a deleterious mitochondrial genome by the mitochondrial UPR” Nature
533(7603):416-9
4. Lin YF, Haynes CM. (2016). “Metabolism and the mitochondrial UPR”, Mol. Cell 61(5):677-82,
review article
5. Haynes CM, Fiorese CJ, Lin YF. (2013). “Evaluating and responding to mitochondrial
dysfunction: the mitochondrial unfolded-protein response and beyond.” Trends Cell Bio
23(7):311-8, review article