Mitochondrial Acetylation Modification in Regulating Drug-Induced Liver

支持的研究的主要目标是研究赖氨酸的乙酰基转移是如何产生的 线粒体蛋白对药物性肝损伤的调节作用。线粒体蛋白质的乙酰化修饰 开始被认为是一种广为流传的；；发现了一种不同的 线粒体代谢途径蛋白。SIRT3是-rna jor nlitchondiral deacynyl&sepahd tp日期 脱乙酰化功能已被认为在多种生物损伤中起作用。氧化还原、遗传毒性 干旱的营养压力源。我们最近发现SIRTSR/-小鼠对对乙酰氨基酚诱导的肝脏具有抵抗力 受伤。我们推测线粒体蛋白乙酰化程度的增加可能在 帝力。我们已经确定了几个新的目标，包括硝基伯醛 脱氢酶2(ALDH2)、细胞凋亡诱导因子(ALF)、三磷酸腺苷合成酶亚基(ATRA)和热 休克蛋白10(HSP10)，在PJLI的发展中被间接地作为靶标。 初步数据还显示，Pr retehtlbh.pf ALDH2活性很高，还有一种L毒醛 水平，在S1RT3-/-小鼠中。此外，我们还表明：在SI RT3r/-小鼠中，去乙酰化bfALDlTliz降低了 有毒的对乙酰氨基酚代谢产物与*tp、ALDH2结合的能力，也已鉴定为：赖氨酸残留物 在Hesfpur假设下，我们将使用‘i^^LDN 2和A作为 探索和描绘线粒体pXteiriacylafion参与调控的Rp[6]指标蛋白 帝力。在拟议的研究中，我们将调查Ly‘sihe乙酰化状态？i Maeetamihopen的作用 (APAP)代谢产物结合及其影响；易感TP‘乙酰氨基酚；肝毒性； 以及ALD‘y2’激活剂(ALDA-1)在APAP中的潜在治疗应用。我们还将 研究AlF.ATPA和d‘PiSPIO在调节醋氨酸肝素酶中的乙酰化状态 相信本研究将揭开胡萝卜蛋白0pfotein乙基化在S使用中的作用 异种生物所致肝损伤。这一生物体的增加将会有Jfoad Hrnplicafihhs，帮助 治疗药物序列的策略/疗法的发展 相关性(请参阅说明)： 药物性肝损伤(DILI)是一个严重的健康问题，具有很高的致死性和资源成本。 最常见的原因是急性肝衰竭--在美国。这项研究计划研究如何 细胞内蛋白质的降解调节药物性肝损伤的敏感性。TWiswiJlpfpvjde波浪 对帝力和pPtenfialiyaici在新战略发展中的机制的见解# Anain.‘st and thtranv for DILI.f PROJEPT/表演站点(S)(如果需要更多空间，请使用

The broad goal of the proppsed research issto investigate how lysine aeetylafiohOTpyifications Pf miiochondrial proteins regulate drug-induced liver injury (DILI). Acetyl modificatipn of mitochondrial proteins is beginning to be recongized as a widespread;;ppst-transla[tipnal rhodificafion, found pn a diverse range of mitochondrial metabolic pathway proteins. SIRT3 is the-rnajor nlitchondiral deacetyl&sepahd tp date its deaeetylation function has been shpwn to play.^^a role in multiple biological insultsfnGl'uding redox, genotoxic arid nutrient stressors. We recenfly found that'SIRTSr/-mice are i-esistant to acetaminophen-induced liver injury. We hypothesize that increased acetylation of mitochondrial proteins might play ariMmportant role in diLI. We have identified sereral npvel SIRT3 dpape^yjatipn targets, including niitpchpridrial aldehyde dehydrogenase 2 (ALDH2), apoptosisririducing factpli(AlF), ATP synthetase arsubunit (ATRa) and heat shock protein 10 (HSP10), which are indirectly iiTiplicated as targets in the develppmehtpf.'PJLI. Our preliminary data additionally shows a greatpr retehtlbh.pf ALDH2 activity, and ,a l-eduetibn-ih toxic aldehyde levels, in S1RT3-/- mice. Furthermore, we show that: in SI RT3r/- mice deacetylatioribfALDlTliz diminished the capacity of toxic acetaminophen metabolites to bind*tp^ALDH2, and also have identified :lysihe residue functioning to this binding modulafiori.TofuitherHesfpur hypothesis, we will employ'i^^LDN2 and A as the index proteins to explore and delineate the rP]6 thatfiipdulation pf mitochondrial pXpteiriacetylafion plays in DILI. In the proposed study, we will and investigate the role of ly'sihe acetylation status?iMaeetamihophen (APAP) metabolite binding, and its effect ori^ALDHMuhetion; suscepfibility tP'acetamihbpheh;hepatotoxicity; and the potential therapeutic application of the ALD'y2'actiyator (Alda-1) in APAP liepatGtPxicity. We will also investigate the acetylation status of AlF.ATPa ahd'PiSPIO in regulating acetaminpp|pn*hepatbt^^ We believe that this study willunmask hovel funGliohs 0 pfotein aeetylation in mbdupingj^s^use|eptibility to xenobiotic-induced liver injury. Increased uhderstahdihli of this biology will have JfoadHrnplicafibhs, aiding the development of strategies/therapies to alieyiatg||ie tyihsequences of drugHn|ucg^ RELEVANCE (See instructions): Drug-induced liver injury (DILI) is a serious health ^problem with high mortatity'ahWresource cost, and is the most common cause ,of acute liver failure-in the USA. This research progranl wNtinyestigate how mpdificatibn of proteins in cells regulates suseeptlbifity to drug-induce liver injury. TWiswiJlpfpvjde ripvel insights infothe mechanism of DILI, and pPtenfialiyaici in the development of new*sgategies#^^^^ anain.'st and thftranv for DILI. f PROJEPT/PERFORMANCE SITE(S) (if additional space Is'needed, use