Targeting Sirtuin-1 to enhance Foxp3+ regulatory T-cell function

靶向 Sirtuin-1 增强 Foxp3 调节 T 细胞功能

• 批准号: 8165446
• 负责人: Ulf Beier
• 金额: $ 13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165446
• 关键词: Ablation; Acetylation; Allografting; Antigenic Switching; Antigens; Attention; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bilateral; Biological Process; Blood Urea Nitrogen; Body Weight decreased; Boxing; Candidate Disease Gene; Cell physiology; Cells; Cellular biology; Colitis; Data; Deacetylation; Development; Diabetes Mellitus; Disease; Disease model; Drug Delivery Systems; Epigenetic Process; Equilibrium; Face; Gene Expression; Genes; Genetic; Graft Rejection; Graft Survival; Heat shock proteins; Heat-Shock Response; Hemorrhage; Histologic; Histology; Histones; IL2RA gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Inbred BALB C Mice; Infection; Inflammatory Bowel Diseases; Islet Cell; Kidney; Kidney Failure; Knock-out; Lead; Learning; Link; Longevity; Lymphocyte; Lysine; Malignant Neoplasms; Measures; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Modeling; Modification; Molecular; Molecular Target; Monitor; Mus; Nephrectomy; Organ; Organ Transplantation; Organ failure; Outcome; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Post-Translational Protein Processing; Protein Acetylation; Proteins; Rag1 Mouse; Recovery; Regulatory T-Lymphocyte; Renal function; Research Personnel; Resistance; Resveratrol; Risk; Role; Self Tolerance; Sodium Dextran Sulfate; Streptozocin; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Translating; Transplantation; Wild Type Mouse; allograft rejection; attenuation; autoreactivity; base; clinically relevant; gastrointestinal; glycemic control; heart allograft; histone acetyltransferase; improved; in vivo; inhibitor/antagonist; insight; islet; kidney allograft; mouse model; neoplastic; new therapeutic target; prevent; protein expression; small molecule; transcription factor

DESCRIPTION (provided by applicant): The immune response requires a delicate balance between activation and attenuation. Likewise, therapies for autoimmune diseases and organ transplantation face the challenge of achieving enough immunosuppression to prevent organ rejection or limit autoreactivity without impairing the host's ability to protect against infections and malignancy. Regulatory T-cells (Treg) are an important T-cell subset crucial to self-tolerance, capable dampening or switching off antigen-specific immune responses (1). The transcription factor Forkheadbox-p3 (Foxp3) plays a key role in the development and functions of Treg. Foxp3 is regulated transcriptionally but also by post-translational modifications. We have shown that acetylation of lysine residues within the Foxp3 protein can enhance Treg function (2). Such acetylation also protects Foxp3 from proteasomal degradation and thus contributes to optimal Treg functions. Foxp3 acetylation is regulated by the competing actions of several histone/protein acetyltransferases (HAT) and histone/protein deacetylases (HDAC). We propose to study the role of Sirtuin-1 (Sirt1), a class III HDAC highly conserved across eukaryotic species and an important mediator of cellular metabolism and longevity, in Tregs. We have begun to exploit use of mice with targeted deletions of Sirt1, which is important as mice with global Sirt1 knockout suffer from metabolic problems and shortened lifespan. In addition, we have employed Sirt1 small molecule inhibitors to test the effect of transient Sirt1 inhibition in wild-type mice. Our preliminary data show that the targeted deletion of Sirt1 increases the acetylation and expression of Foxp3, and enhances the immunosuppressive functions of Treg. In addition, deletion of Sirt1 in Tregs, or its pharmacologic inhibition, attenuates allograft rejection and prolongs survival of murine cardiac allografts. Therefore, our central hypothesis is that targeting Sirt1 may have therapeutic value in autoimmunity and transplantation. Our aims are to explore how Sirt1 deletion or inhibition: 1) improves allograft survival and function (in murine recipients with induced diabetes and renal failure); 2) alleviates autoimmunity (in murine inflammatory bowel disease models); and, further, understand 3) distinct molecular mechanisms how Sirt1 influences T-cell biology beyond simply promoting Foxp3 acetylation. Our findings will likely prove important to the development of new immunomodulatory strategies for application in autoimmunity and transplantation. Our proposed studies are also important for an increased understanding of the functions of Sirt1 in immune responses, given the rising attention being given to the Sirt1 activator resveratrol (already available over the counter) and other more potent small molecule Sirt1 activators (3), for therapy of various diseases and for promotion of overall well-being. In addition, Sirt1 inhibitors are under consideration as anti-neoplastic drugs (4). Therefore, we caution that it is critical to learn more about the role of Sirt1 in the immune system as such treatment options are evolving. PUBLIC HEALTH RELEVANCE (provided by applicant): We study Sirtuin-1 as a novel therapeutic target to attenuate the immune response, which is relevant to improve treatment options to achieve immunosuppression, e.g. for patients suffering from self-reactive immune disease, or recipients of an organ transplant. Furthermore, it is important to learn more about the role of Sirtuin-1 in the immune system, as many investigators pursue Sirtuin-1 enhancement (diabetes mellitus, metabolic syndrome), or Sirtuin-1 suppression (certain cancers).

描述(由申请人提供)：免疫反应需要在激活和衰减之间取得微妙的平衡。同样，自身免疫性疾病和器官移植的治疗也面临着挑战，即在不损害宿主抵御感染和恶性肿瘤的能力的情况下，实现足够的免疫抑制，以防止器官排斥或限制自身反应。调节性T细胞(Treg)是一种重要的T细胞亚群，对自我耐受至关重要，能够抑制或关闭抗原特异性免疫反应。转录因子Forkhead box-p3(Foxp3)在Treg的发育和功能中起着关键作用。Foxp3受转录调控，但也受翻译后修饰的影响。我们已经证明，Foxp3蛋白中赖氨酸残基的乙酰化可以增强Treg功能(2)。这种乙酰化还可以保护Foxp3免受蛋白酶体的降解，从而有助于实现最佳的Treg功能。Foxp3乙酰化受多种组蛋白/蛋白乙酰基转移酶(HAT)和组蛋白/蛋白去乙酰基酶(HDAC)相互竞争作用的调节。我们建议研究Sirtuin-1(Sirt1)在Tregs中的作用。Sirt1是一种在真核生物中高度保守的III类HDAC，是细胞代谢和寿命的重要调节因子。我们已经开始利用靶向Sirt1基因缺失的小鼠，这一点很重要，因为全局Sirt1基因敲除的小鼠患有新陈代谢问题，寿命缩短。此外，我们还使用了Sirt1小分子抑制剂来测试Sirt1在野生型小鼠中的瞬时抑制效果。我们的初步数据显示，Sirt1的靶向缺失增加了Foxp3的乙酰化和表达，并增强了Treg的免疫抑制功能。此外，Tregs中Sirt1的缺失或其药物抑制，可以减轻同种异体心脏移植物的排斥反应，延长小鼠异基因心脏移植物的存活时间。因此，我们的中心假设是靶向Sirt1可能在自身免疫和移植中具有治疗价值。我们的目标是探索Sirt1缺失或抑制如何：1)提高同种异体移植物的存活率和功能(在伴有糖尿病和肾功能衰竭的小鼠受者中)；2)减轻自身免疫(在小鼠炎症性肠病模型中)；以及，进一步了解Sirt1如何影响T细胞生物学的不同分子机制，而不仅仅是促进Foxp3乙酰化。我们的发现可能对开发新的免疫调节策略应用于自身免疫和移植具有重要意义。我们建议的研究对于进一步了解Sirt1在免疫反应中的作用也很重要，因为人们越来越关注Sirt1激活剂白藜芦醇(已在柜台上获得)和其他更有效的小分子Sirt1激活剂(3)，用于治疗各种疾病和促进整体福祉。此外，Sirt1抑制剂正在被考虑作为抗肿瘤药物(4)。因此，我们警告说，随着这种治疗方案的演变，更多地了解Sirt1在免疫系统中的作用是至关重要的。 公共卫生相关性(由申请人提供)：我们研究Sirtuin-1作为一种新的治疗靶点来减弱免疫反应，这与改进治疗方案以实现免疫抑制有关，例如对于患有自身反应性免疫疾病的患者或器官移植的接受者。此外，更多地了解Sirtuin-1在免疫系统中的作用是很重要的，因为许多研究人员正在研究Sirtuin-1增强(糖尿病、代谢综合征)或Sirtuin-1抑制(某些癌症)。