14C AS A MARKER FOR BETA CELL TURNOVER IN ADULT HUMANS

14C 作为成年人 β 细胞更新的标志

• 批准号: 7359014
• 负责人: DAVID M HARLAN
• 金额: $ 1.47万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359014
• 关键词: 14C; MARKER; BETA; CELL; TURNOVER

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type I diabetes mellitus (T1DM) results from an immune mediated destruction of the insulin producing beta cells (beta-cells) located in the pancreas in cell clusters called the islets of Langerhans. Since beta-cells are the only cells in the body that physiologically regulate and secrete insulin, their destruction causes a chronic disease state which necessitates frequent blood glucose monitoring and exogenous insulin therapy. It is very difficult but important for patients to maintain near normal blood glucose levels since high glucose levels are associated with severe end organ complications. These complications include renal failure, blindness, neuropathy, and large vessel atherosclerotic diseases like ischemic heart disease and stroke. Strategies that could promote beta-cell recovery or regeneration would represent an important therapeutic advance. Other investigators are attempting to develop an alternative source of insulin producing cells. However, while the question is critically important, whether the adult human pancreas can regenerate beta-cells remains unknown. For instance, if significant beta-cell regeneration is possible during post-natal or adult life, then strategies aiming to disrupt the autoimmune process underlying T1DM might reverse the disease. Additionally, data supporting beta-cell regeneration would support to the notion that adult pancreatic stem cells exist and would support the search for such stem cells. Our hypothesis is that the adult pancreas maintains the capacity to continuously generate new beta-cells. Since changing atmospheric 14C levels (secondary to nuclear testing) over the past half century have been accurately tracked, the 14C incorporated into a tissue's DNA can be used to quantitate the age of that DNA (i.e. when that DNA was made) and thus the turnover rate of cells within that tissue. For example, this AMS 14C measurement within DNA has shown a surprising cell turnover rate in the human brain. We seek to test our hypothesis that beta-cells too are "turning over" by applying the AMS technique to measure 14C within cadaveric donor beta-cell DNA. AMS measurement of 14C in beta-cells of humans of different ages should enable us to answer whether beta-cells regenerate in adult humans. Data suggesting that beta-cells regenerate in adult human pancreata would promote research designed to further promote that process, and would spur efforts to identify the progenitor cell for the new beta-cells. Alternatively, if we find no evidence suggesting new beta-cells are created during adulthood, efforts would more appropriately be directed towards finding new sources for insulin producing cells (e.g. embryonic stem cells, cellular therapy, etc.).

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。 I 型糖尿病 (T1DM) 是由于免疫介导的胰岛细胞簇（称为胰岛）中产生胰岛素的 β 细胞（β 细胞）遭到破坏所致。由于β细胞是体内唯一在生理上调节和分泌胰岛素的细胞，它们的破坏会导致慢性疾病状态，从而需要频繁的血糖监测和外源性胰岛素治疗。对于患者来说，维持接近正常的血糖水平非常困难但很重要，因为高血糖水平与严重的终末器官并发症相关。这些并发症包括肾衰竭、失明、神经病变和大血管动脉粥样硬化性疾病，如缺血性心脏病和中风。能够促进β细胞恢复或再生的策略将代表着重要的治疗进展。其他研究人员正在尝试开发胰岛素产生细胞的替代来源。然而，尽管这个问题至关重要，但成人胰腺是否能够再生β细胞仍然未知。例如，如果在产后或成年期间可能出现显着的 β 细胞再生，那么旨在破坏 T1DM 潜在的自身免疫过程的策略可能会逆转该疾病。此外，支持β细胞再生的数据将支持成体胰腺干细胞存在的观点，并将支持对此类干细胞的研究。我们的假设是，成人胰腺保持持续产生新β细胞的能力。由于过去半个世纪以来大气 14C 水平的变化（继核试验之后）已被准确追踪，因此掺入组织 DNA 中的 14C 可用于量化该 DNA 的年龄（即该 DNA 的生成时间），从而确定该 DNA 的周转率。该组织内细胞的比率。例如，DNA 内的 AMS 14C 测量显示人脑中令人惊讶的细胞更新率。我们试图通过应用 AMS 技术测量尸体供体 β 细胞 DNA 中的 14C 来检验我们的假设，即 β 细胞也在“转变”。 AMS 对不同年龄的人类 β 细胞中 14C 的测量应该使我们能够回答成年人体内 β 细胞是否再生。表明β细胞在成人胰腺中再生的数据将促进旨在进一步促进该过程的研究，并将刺激鉴定新β细胞的祖细胞的努力。或者，如果我们没有发现任何证据表明在成年期间会产生新的β细胞，那么更合适的努力应该是寻找胰岛素产生细胞的新来源（例如胚胎干细胞、细胞疗法等）。