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研究方向: 蛋白质稳态与疾病

神经退行性疾病,例如肌萎缩侧所硬化症、老年痴呆症、帕金森综合症等,严重影响着老年群体的健康。当构象异常的特定蛋白发生不可逆聚集时,会造成特定脑区神经细胞的进行性功能失调,进而导致机体发生神经病退行性变。

伴随着衰老进程出现的蛋白质质量控制和降解系统的紊乱是导致致病蛋白聚积的主要原因。因此,张在荣课题组致力于阐明错误折叠的蛋白以及其它致病蛋白在细胞内降解的分子机制。我们的研究将会加深解衰老导致的蛋白稳态的失调的基本原理,并对神经退行性疾病的预防和干预提供新的思路和药物靶标。

 

1、阐明与错误折叠蛋白合成、降解、和聚集相关通路的分子机制。

真核生物通过内质网相关的蛋白降解途径清除无用的蛋白从而保持细胞内蛋白质的稳态和平衡。尽管对这一过程的研究在过去十年间取得了一些进展,但很多基础问题仍然未能研究清楚。张在荣课题组通过体内、体外等实验方法对有害蛋白的合成和降解机制进行深入研究,以揭示错误折叠蛋白的降解对细胞乃至个体的重要性。我们实验室的长期目标是探索并发现清除错误折叠蛋白在细胞内聚积的基本原理,并根据原理寻找预防或干预策略,以期降低有害蛋白对细胞及机体产生的负面作用。

 

2、鉴定病理条件下调控细胞内蛋白质稳态的新因子和靶点。

当前,蛋白质降解的检测多采用非天然底物或者疾病相关的突变蛋白作为底物。由于已经发现的内源性降解底物数量有限,所以我们对生理状态下蛋白的降解知之甚少。张在荣研究组采用基因组学、生物化学、蛋白质组学相结合的方法,研究内质网蛋白在细胞中不同生理、病理条件下的丰度变化,从而鉴定调控内质网蛋白质稳态的关键分子,例如泛素E3连接酶和去泛素化酶等,从而找到潜在的药物靶点;并根据这些靶点来筛选活性小分子调节剂。这些研究有助于我们发现新的与疾病相关的蛋白质分子,从而揭示蛋白降解与其他细胞通路之间的相互作用,并开发小分子探针来研究或干预相关的疾病。

 

3、内质网应激机制与神经退行性疾病。

未折叠蛋白响应(UPR)是主要的内质网质量控制系统之一,其感受内质网应激信号并通过改变细胞内的转录和翻译来维持内质网稳态。已知UPR能在多种生理条件下发挥功能,与糖尿病、癌症、衰老、神经退行性疾病等人类疾病有重要关联。但是,在不同生理条件下,如:蛋白合成增加,脂质水平升高,己糖胺水平过高或过低时,UPR是如何被调节的我们还知之甚少。张在荣课题组采用全基因组筛选的方法寻找哺乳动物细胞中与Ire1-. PERK-, ATF6-三大UPR分支有关的新因子。这些研究有助于发现并鉴定与哺乳动物内质网应激相关的新的因子,并为糖尿病、癌症、衰老等人类疾病提供的治疗提供潜在的靶点。

 

 

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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