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; 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 等待名单上肾脏移植候选者的数量每年继续增加，而 肾脏捐赠数量仍然停滞不前。持久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 年长的捐助者具有更高的延迟移植功能和移植物损失的风险。虽然被认为是ECD肾脏 回顾性研究提高了风险，表明评估肾脏质量的现有系统较低 预测能力导致ECD移植功能和相关患者的生存差异很大。 确定可以评估ECD移植质量并预测移植功能的新因素，将允许扩展 供体池并最大程度地减少器官丢弃，而不会损害患者的预后。复制的下降 某些自我更新细胞的能力和衰老细胞的积累似乎有助于 组织老化。衰老细胞缺乏复制能力，因此不能导致组织修复和 稳态。通过与 肾脏移植手术，导致较早的移植失败。此外，衰老细胞保持代谢 活跃并分泌无数的促炎细胞因子，导致组织炎症。所以， 已经建议测量体内衰老细胞的积累，以提供一种测量方法 “分子老化”。在2004年，Sharpless实验室提出了使用P16INK4A表达的Sharpless实验室，这是细胞的关键效应。 衰老，作为人类分子衰老的体内标记。该标记周围的知识产权是 于2012年发行，是HealthSpan诊断的核心技术。 p16ink4a标记，以 血液在> 1,000名人类患者的许多临床情况下进行了评估，并且似乎提供了 与其他在体内测量衰老的方法相比，几种重要的技术优势。 p16ink4a 诊断可能在肾脏移植物评估中特别有用，因为在肾脏中的P16INK4A水平 器官收获是手术后6个月至1年的肾脏同种异体功能最著名的预测指标。这 发现肾脏p16Ink4a表达比供体年龄更好地预测了移植功能的预测指标，进一步支持了我们 理论认为P16INK4A诊断可以大大改善移植物评估并允许老年患者捐赠 肾脏进行移植，明显扩大了供体池并减少器官丢弃。在这个 提案，我们将确定P16INK4A血液测试是否与移植功能相似，类似于肾脏P16INK4A 表达。廉价，易于使用的血液测试的可用性会增加采用的机会 诊所。该阶段I建议的完成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分析进行商业化。