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研究方向: 蛋白質穩態與疾病

神經退行性疾病,例如肌萎縮側所硬化癥、老年癡呆癥、帕金森綜合癥等,嚴重影響著老年群體的健康。當構象異常的特定蛋白發生不可逆聚集時,會造成特定腦區神經細胞的進行性功能失調,進而導致機體發生神經病退行性變。

伴隨著衰老進程出現的蛋白質質量控制和降解系統的紊亂是導致致病蛋白聚積的主要原因。因此,張在榮課題組致力于闡明錯誤折疊的蛋白以及其它致病蛋白在細胞內降解的分子機制。我們的研究將會加深解衰老導致的蛋白穩態的失調的基本原理,并對神經退行性疾病的預防和干預提供新的思路和藥物靶標。

 

1、闡明與錯誤折疊蛋白合成、降解、和聚集相關通路的分子機制。

真核生物通過內質網相關的蛋白降解途徑清除無用的蛋白從而保持細胞內蛋白質的穩態和平衡。盡管對這一過程的研究在過去十年間取得了一些進展,但很多基礎問題仍然未能研究清楚。張在榮課題組通過體內、體外等實驗方法對有害蛋白的合成和降解機制進行深入研究,以揭示錯誤折疊蛋白的降解對細胞乃至個體的重要性。我們實驗室的長期目標是探索并發現清除錯誤折疊蛋白在細胞內聚積的基本原理,并根據原理尋找預防或干預策略,以期降低有害蛋白對細胞及機體產生的負面作用。

 

2、鑒定病理條件下調控細胞內蛋白質穩態的新因子和靶點。

當前,蛋白質降解的檢測多采用非天然底物或者疾病相關的突變蛋白作為底物。由于已經發現的內源性降解底物數量有限,所以我們對生理狀態下蛋白的降解知之甚少。張在榮研究組采用基因組學、生物化學、蛋白質組學相結合的方法,研究內質網蛋白在細胞中不同生理、病理條件下的豐度變化,從而鑒定調控內質網蛋白質穩態的關鍵分子,例如泛素E3連接酶和去泛素化酶等,從而找到潛在的藥物靶點;并根據這些靶點來篩選活性小分子調節劑。這些研究有助于我們發現新的與疾病相關的蛋白質分子,從而揭示蛋白降解與其他細胞通路之間的相互作用,并開發小分子探針來研究或干預相關的疾病。

 

3、內質網應激機制與神經退行性疾病。

未折疊蛋白響應(UPR)是主要的內質網質量控制系統之一,其感受內質網應激信號并通過改變細胞內的轉錄和翻譯來維持內質網穩態。已知UPR能在多種生理條件下發揮功能,與糖尿病、癌癥、衰老、神經退行性疾病等人類疾病有重要關聯。但是,在不同生理條件下,如:蛋白合成增加,脂質水平升高,己糖胺水平過高或過低時,UPR是如何被調節的我們還知之甚少。張在榮課題組采用全基因組篩選的方法尋找哺乳動物細胞中與Ire1-. PERK-, ATF6-三大UPR分支有關的新因子。這些研究有助于發現并鑒定與哺乳動物內質網應激相關的新的因子,并為糖尿病、癌癥、衰老等人類疾病提供的治療提供潛在的靶點。

 

 

Proteostasisand Neurodegeneration

 

Neurodegenerativediseases such as Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and Parkinson’sdisease are devastating and influence a large number of individuals in theaging population. These diseases are caused by the progressive dysfunction ofspecific neurons in selective regions of the brain due to the accumulation ofspecific proteins with aberrant conformation.

 

Thedeposition of these diseases-causing proteins is largely due to failure ofprotein quality control and degradation systems that usually happenedconcomitant with aging. Therefore, Zhang’sresearch group aims to elucidate the cellular mechanisms involved in thedegradation of misfolded and detrimental proteins. Our research will contributesignificantly to the understanding of the age-onset decline of proteostasis andthus help to combat neurodegenerative diseases and aging.

 

1.      Understandingthe mechanistic basis of misfolded protein degradation and deposition pathway.

The eukaryotic ER maintains proteinhomeostasis by eliminating unwanted proteins by the ER-associated degradation(ERAD) pathway. Despite advances in past decades, many fundamental questionsremain unclear. Zhang’s research will be focused on several aspects of aberrantprotein degradation that range from mechanistic studies in vitro to analysis of its importance in cells and animals. Thelong-term goal of our lab is to understand the principles that govern theclearance and deposition of misfolding-prone proteins, and to identifystrategies that could reduce the burden of damaged proteins for cells and organisms.

 

2.      Identifyingnovel components that regulate cellular protein homeostasis underpathophysiological conditions.

To date, protein degradation is oftenexamined using artificial substrates or disease relevant mutant proteins. Dueto the presence of limited number of endogenous substrates, the importance ofprotein destruction under physiological conditions has been poorly understood.By using multiple genomic, biochemical, and proteomic strategies, Zhang’sresearch group is currently investigating ER protein abundance at various conditionsin cells (e.g., elevated or decreased protein degradation capacity). This willlead to discovery of new protein components (e.g., those prone to be misfoldedand degraded) that could be involved in ageing, and thus will uncover theinterplay of protein degradation and other cellular pathways.

 

3.    Mechanism of ER stress response and neurodegenerativediseases.

Unfolded protein response (UPR) is akey quality control system that senses ER stress signals and initiates globalchanges in transcription and translation to maintain ER homeostasis. It is nowevident that UPR functions in various physiological conditions, and are masterregulators of human disorders including diabetes, cancer, aging, andneurodegeneration. However, little is known about how UPR is modulated undervarious physiological conditions, such as increased protein synthesis, elevatedlevels of lipids, and high or low hexosamine levels. Zhang’s lab is performinga genome wide screen for components that are involved in the Ire1-, PERK-, andATF6-UPR branches in mammalian cells. These studies will identify novel factorsthat are involved in the ER stress response in mammalian cells, and willprovide promising therapeutic targets for the treatment of human diseases, suchas diabetes, cancer and aging.

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