Mitochondrial Acetylation Modification in Regulating Drug-Induced Liver

所提出的研究的广泛目标是研究赖氨酸乙酰化是如何使Pf 微血管蛋白调节药物诱导的肝损伤（DILI）。线粒体蛋白的乙酰化修饰 正开始被认为是一种广泛的;; ppst-transla [tipnal rhodificafion，found pn a variety of 线粒体代谢途径蛋白。SIRT3是一种主要的去乙酰基和去磷酸化的蛋白质， 脱乙酰基功能已被shpwn发挥。^^在氧化还原、遗传毒性等多种生物损伤中发挥作用 干旱养分胁迫我们最近发现SIRTSr/-小鼠对醋氨酚诱导的肝损伤有抵抗作用 损伤我们推测线粒体蛋白质乙酰化的增加可能在 迪利。我们已经确定了一些新的SIRT3靶点，包括硝基苯甲醛， 脱氢酶2（ALDH 2）、腺苷酸合成酶亚基（ATRa）和热诱导因子（AlF）。 休克蛋白10（HSP 10），其在开发过程中被间接地作为靶标。PJLI。我们 初步的数据还显示了ALDH 2的活性很高，并且， 在S1RT3-/-小鼠中的水平。此外，我们表明：在SIRT3r/-小鼠中，去乙酰化的ALDlTliz减少了 毒性对乙酰氨基酚代谢物结合 * tp^ALDH 2的能力，并且还鉴定了： 为了进一步的Hesfpur假设，我们将使用LDN2和A作为结合调节剂。 索引蛋白质，以探索和描绘线粒体pX蛋白乙酰化的调控在 DILI。在拟议的研究中，我们将和调查的作用ly 'sihe乙酰化状态？依他米酚 （APAP）代谢物结合及其对ALDH的影响;对乙酰氨基酚的增敏性;肝毒性; 以及ALD γ 2 ′激活剂（Alda-1）在APAP肝硬化治疗中的潜在应用。我们还将 研究AlF.ATPa和PiSPIO在调节乙酰氨基的乙酰化状态|pn * hepbt ^^我们 我相信，这项研究将揭示Hovel在合成中的乙酰化作用，|对...的敏感性 外源性肝损伤增加的这种生物体的uhderstahdihli将有JfoadHrnplicahs，帮助 制定战略/疗法，||即药物的序列|UCG ^ 相关性（参见说明）： 药物性肝损伤（DILI）是一种严重的健康问题，具有高死亡率和资源成本， 最常见的原因，急性肝衰竭-在美国。这项研究计划将对 细胞中蛋白质的缺陷调节对药物诱导的肝损伤的易感性。TwiswiJlpffjde ripvel 关于DILI机制的见解，以及在新药物开发中的应用#^ anain。"st和thftranv为DILI。F 项目/演出现场（如果需要额外空间，

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