Novel Short ACE2 variant for Delayed Graft Function

用于延迟移植功能的新型短 ACE2 变体

• 批准号: 10514607
• 负责人: DANIEL BATLLE
• 金额: $ 12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514607
• 关键词: ACE2; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Affect; Albumins; Allogenic; Amino Acids; Angiotensins; Attenuated; Binding; Biomedical Engineering; Cessation of life; Chimeric Proteins; Clinical; Data; Dialysis procedure; Enzymes; FDA approved; Fostering; Genetic Models; Goals; Health Expenditures; Hour; Human; Hypotension; Infusion procedures; Injury; Ischemia; Kidney; Kidney Transplantation; Lysine; Modeling; Mus; Organ; Patients; Peptides; Perfusion; Phenylalanine; Prevention; Production; Property; Proteins; Proximal Kidney Tubules; Renal Circulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Testing; Therapeutic Effect; Tissues; Transplant Recipients; Tubular formation; Urine; Variant; absorption; allograft rejection; delayed graft function; driving force; glomerular filtration; hemodynamics; high risk; improved; molecular size; mouse model; novel; novel strategies; prevent; protective effect; tool

Project summary Delayed graft function (DGF) is a form of acute kidney injury clinically defined as the need for dialysis within one week of kidney transplantation. It affects up to 50% of deceased-donor kidney transplant recipients. Because of the organ shortage crisis, marginal or expanded criteria donor kidneys are increasingly considered even though these kidneys are at higher risk to develop DGF. Patients with DGF have a higher risk of allograft rejection and death. DGF is largely caused by acute proximal tubular injury induced by ischemia. There are no FDA-approved treatments available to date. Treatment or prevention of delayed graft function, therefore, poses an unmet clinical need and new approaches to prevent and attenuate DGF are urgently needed. In this proposal, we want to examine the preventative value of administering a shorter angiotensin converting enzyme 2 (ACE2) variant . We have preliminary data that a short mouse ACE2 variant protects against acute kidney injury (AKI) caused by ischemia reperfusion injury (IRI). As ischemia reperfusion injury is the driving force of DGF, we propose that a novel short human ACE2 variant can prevent and attenuate DGF. ACE2 is a tissue enzyme abundant in the kidneys that cleaves the amino acid phenylalanine to form Angiotensin (Ang) (1- 7) from Ang II (Ang (1-8)). In a genetic model of ACE2 deficiency, AKI induced by ischemia-reperfusion is aggravated and moreover a decrease in kidney ACE2 activity has been reported in AKI which leads to less formation of Ang 1-7 from Ang II. Therefore, there is a rationale for administering ACE2 to the kidney with AKI and by extension to prevent / attenuate DGF. We propose to examine the potential preventative / therapeutic effect of a novel human ACE2 variant which is shorter than the native soluble ACE2 and therefore filterable across the glomerular filtration barrier such that it can be taken up by the kidney proximal tubule where it fosters the degradation of Ang II and the formation of Ang 1-7. With this approach, the formation of Ang II continues, such that the systemic and renal circulation can be sustained by this critical peptide without causing hypotension or compromising glomerular hemodynamics. We have fused our shorter human ACE2 variant with an Albumin binding domain (ABD), as a strategy to extend the duration of action from hours to days. We plan to examine if in mice with syngeneic kidney transplantation administration of this novel ACE2 variant to the recipient that has received a graft subjected to 4 hours of cold ischemia will improve delayed graft function and increase kidney ACE2 activity. Additionally, it will be examined if perfusion of the kidney graft ex vivo with this ACE2 variant prior to kidney transplantation protects against delayed graft function.

项目摘要 延迟移植功能（DGF）是临床上急性肾脏损伤的一种形式 肾脏移植一周。它影响多达50％的死者肾脏移植受者。由于 器官短缺危机，边际或扩展的标准供体肾脏越来越多地考虑 这些肾脏有开发DGF的风险更高。 DGF患者患同种异体移植排斥的风险更高， 死亡。 DGF在很大程度上是由缺血诱导的急性近端管状损伤引起的。 迄今为止，没有FDA批准的治疗方法。治疗或预防延迟移植功能， 因此，迫切需要构成未满足的临床需求，并迫切需要预防和减轻DGF的新方法。 在此提案中，我们想检查施用短血管紧张素转换的预防价值 酶2（ACE2）变体。我们有初步的数据，即短鼠ACE2变体可以防止急性 缺血再灌注损伤引起的肾脏损伤（AKI）。由于缺血再灌注损伤是驱动力 在DGF中，我们建议一种新型的短人ACE2变体可以预防和衰减DGF。 ace2是一个 在肾脏中丰富的组织酶，该酶裂解氨基酸苯丙氨酸形成血管紧张素（ANG）（1- 7）来自Ang II（ANG（1-8））。在ACE2缺乏症的遗传模型中，缺血 - 灌注诱导的AKI是 据报道，AKI的肾脏ACE2活性的加重和降低，导致较少 ANG II的ANG 1-7形成。因此，使用AKI对肾脏进行ACE2有一个理由 并扩展以防止 /衰减DGF。 我们建议研究一种新型人ACE2变体的潜在预防 /治疗作用 比天然可溶ACE2短，因此可以在肾小球滤过屏障上过滤，这样它就可以 可以用肾脏近端小管占用，在该小管中促进ANG II的降解和形成 ANG 1-7。通过这种方法，ANG II的形成继续，使系统和肾脏循环可以 通过这种关键的肽维持，而不会引起低血压或损害肾小球血流动力学。 我们已经将较短的人类ACE2变体与白蛋白结合域（ABD）融合在一起，作为扩展的策略 几个小时到几天的行动持续时间。我们计划检查是否具有同性肾移植的小鼠 给予接收者4小时的移植物的接收者，将这种新颖的ACE2变体的给药 缺血将改善延迟的移植功能并增加肾脏ACE2活性。此外，将进行检查 如果在肾脏移植之前使用此ACE2变体的肾脏移植物灌注会预防 延迟移植功能。