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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 I型糖尿病（T1 DM）是由免疫介导的对位于胰腺中称为朗格汉斯岛的细胞簇中的胰岛素产生β细胞（β细胞）的破坏引起的。 由于β细胞是体内唯一的生理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，这需要频繁的血糖监测和外源性胰岛素治疗。由于高血糖水平与严重的终末器官并发症相关，因此患者维持接近正常的血糖水平非常困难，但也很重要。 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疾病，如缺血性心脏病和中风。可以促进β细胞恢复或再生的策略将代表重要的治疗进展。其他研究人员正在试图开发一种替代来源的胰岛素产生细胞。然而，尽管这个问题至关重要，但成人胰腺是否可以再生β细胞仍然是未知的。 例如，如果在出生后或成年期可能发生显著的β细胞再生，那么旨在破坏T1 DM相关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人胰腺干细胞存在的概念，并将支持对此类干细胞的研究。 我们的假设是，成年胰腺保持不断产生新β细胞的能力。由于在过去的半个世纪中不断变化的大气14 C水平（继发于核试验）已经被准确地跟踪，因此掺入组织DNA中的14 C可以用于定量该DNA的年龄（即，该DNA是何时产生的），从而定量该组织中细胞的周转率。 例如，DNA中的AMS 14 C测量显示了人类大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14 C来测试我们的假设，即β细胞也在“翻转”。AMS对不同年龄人类β细胞中14 C的测量应该使我们能够回答β细胞是否在成年人中再生。数据表明，β细胞在成人胰腺中再生将促进旨在进一步促进这一过程的研究，并将刺激识别新β细胞祖细胞的努力。 或者，如果我们没有发现证据表明成年期产生了新的β细胞，那么更合适的努力将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）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 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.).