A biomarker of aging as a predictor of kidney transplant function

衰老生物标志物作为肾移植功能的预测因子

• 批准号: 8714362
• 负责人: Natalia Mitin
• 金额: $ 12.16万
• 依托单位: SAPERE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714362
• 关键词: Activities of Daily Living; Adoption; Age; Aging; Aging-Related Process; Am 80; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; CDKN2A gene; Categories; Cell Aging; Cells; Clinic; Clinical; Clinical Trials; Complex; DNA Damage; Data; Defect; Diagnostic; Elderly; Epigenetic Process; Evaluation; Face; Funding; Genes; Growth; Harvest; Healed; Histocompatibility Testing; Homeostasis; Hour; Human; IL6 gene; Immune System Diseases; Impaired wound healing; Individual; Inflammation; Inflammatory; Intellectual Property; Kidney; Kidney Transplantation; Lead; Length; Life; Malignant Neoplasms; Measures; Messenger RNA; Methods; Molecular; Names; Normal Cell; Operative Surgical Procedures; Organ; Organ Donor; Organ Harvestings; Organism; Outcome; Oxidative Stress; Patients; Phase; Phenotype; Renal Tissue; Renal function; Retrospective Studies; Risk; Small Business Innovation Research Grant; Smoking; Stimulus; Stress; System; T-Lymphocyte; Technology; Telomere Shortening; Time; Tissues; Transplantation; Tumor Suppressor Proteins; Waiting Lists; base; commercialization; cost; cytokine; delayed graft function; graft failure; graft function; healing; high risk; improved; in vivo; indexing; kidney allograft; molecular marker; older patient; peer; peripheral blood; public health relevance; regenerative; response; sarcopenia; self renewing cell; senescence; telomere; theories; tissue regeneration; tissue repair

ABSTRACT The number of kidney transplant candidates on the waiting list continues to increase each year, while the number of kidney donations remains stagnant. The enduring donor shortage compels clinicians to use kidneys from marginal donors, referred to as expanded criteria donors (ECD). ECD kidneys, obtained primarily from older donors, have a higher risk of delayed graft function and graft loss. While ECD kidneys are thought to carry increased risks, retrospective studies suggest that the existing system to evaluate kidney quality has low predictive power resulting in a large variability in ECD graft functions and the associated patient survival. Identification of new factors that can assess ECD graft quality and predict graft function, would allow to expand donor pool and to minimize organ discard without compromising patient outcomes. A decline in the replicative capacity of certain self-renewing cells and accumulation of senescent cells appears to broadly contribute to tissue aging. Senescent cells lack replicative capacity and, therefore, cannot contribute to tissue repair and homeostasis. This defect in tissue regenerative potential is further accelerated by stresses associated with kidney transplant surgeries, leading to an earlier graft failure. Moreover, senescent cells remain metabolically active and secrete a myriad of pro-inflammatory cytokines, contributing to tissue inflammation. Therefore, measuring the accumulation of senescent cells in vivo has been suggested to provide a means of measuring 'molecular aging'. In 2004, the Sharpless lab proposed using expression of p16INK4a, a key effector of cellular senescence, as an in vivo marker of molecular aging in humans. Intellectual property around this marker was issued in 2012 and is the core technology of HealthSpan Diagnostics. The p16INK4a marker, measured in blood, has been evaluated in a number of clinical scenarios in >1,000 human patients and appears to offer several significant technical advantages over other approaches to measuring senescence in vivo. The p16INK4a diagnostic could be especially useful in kidney graft assessment as p16INK4a levels in the kidney at the time of organ harvest are the best known predictor of renal allograft function 6 months to 1 year after surgery. The finding that renal p16INK4a expression is a better predictor of graft function than donor age further supports our theory that p16INK4a diagnostic could greatly improve graft assessment and allow older patients to donate kidneys for transplantation, markedly expanding the donor pool and decreasing organ discard. In this proposal, we will determine if p16INK4a blood test correlates with graft function similarly to kidney p16INK4a expression. The availability of inexpensive, easy to use blood test would increase chances of adoption into the clinic. Completion of this Phase I proposal will allow us to seek Phase II funding to conduct large scale clinical trials and further develop our p16INK4a assay for commercialization.

抽象的 等待名单上的肾移植候选者数量每年持续增加，而 肾脏捐赠的数量仍然停滞不前。持续的供体短缺迫使临床医生使用肾脏 来自边际捐助者，称为扩展标准捐助者（ECD）。 ECD 肾脏，主要来自 年龄较大的捐赠者，移植物功能延迟和移植物丢失的风险较高。虽然 ECD 肾脏被认为 风险增加，回顾性研究表明，现有的肾脏质量评估系统效率较低 预测能力导致 ECD 移植物功能和相关患者生存率存在很大差异。 确定可以评估 ECD 移植物质量和预测移植物功能的新因素，将有助于扩大 捐献者库并在不影响患者预后的情况下最大限度地减少器官丢弃。复制能力下降 某些自我更新细胞的能力和衰老细胞的积累似乎广泛有助于 组织老化。衰老细胞缺乏复制能力，因此无法促进组织修复和 体内平衡。与组织再生潜力相关的压力进一步加速了这种缺陷 肾移植手术，导致早期移植失败。此外，衰老细胞仍保持代谢状态。 活跃并分泌大量促炎细胞因子，导致组织炎症。所以， 有人建议测量体内衰老细胞的积累提供一种测量方法 “分子老化”。 2004 年，Sharpless 实验室提出使用 p16INK4a 的表达，p16INK4a 是细胞的关键效应子。 衰老，作为人类分子衰老的体内标志。围绕该标记的知识产权是 于2012年发布，是HealthSpan Diagnostics的核心技术。 p16INK4a 标记，测量于 血液，已在超过 1,000 名人类患者的多种临床场景中进行了评估，似乎提供了 与其他测量体内衰老的方法相比，具有几个显着的技术优势。 p16INK4a 诊断在肾移植评估中特别有用，因为移植时肾脏中的 p16INK4a 水平 器官采集是术后 6 个月至 1 年内肾同种异体移植功能最知名的预测指标。这 发现肾脏 p16INK4a 表达比供体年龄更能预测移植物功能，这进一步支持了我们的研究 p16INK4a 诊断可以极大改善移植物评估并允许老年患者捐献的理论 用于移植的肾脏，显着扩大了供体库并减少了器官丢弃。在这个 建议，我们将确定 p16INK4a 血液测试是否与移植功能相关，类似于肾脏 p16INK4a 表达。廉价、易于使用的血液检测的可用性将增加采用的机会 诊所。完成第一阶段提案将使我们能够寻求第二阶段资金来进行大规模临床 试验并进一步开发我们的 p16INK4a 检测以实现商业化。