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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。1型糖尿病（T1DM）是由免疫介导的胰岛素生成细胞（β细胞）的破坏引起的，这些细胞位于被称为朗格汉斯岛的胰腺细胞群中。由于β -细胞是体内唯一的生理调节和分泌胰岛素的细胞，它们的破坏导致慢性疾病状态，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，但也很重要，因为高血糖水平与严重的终末器官并发症有关。这些并发症包括肾衰竭、失明、神经病变和大血管粥样硬化性疾病，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是一项重要的治疗进步。其他研究人员正试图开发一种胰岛素生成细胞的替代来源。然而，尽管这个问题至关重要，但成人胰腺是否能再生β细胞仍然未知。例如，如果显著的β细胞再生在产后或成年期是可能的，那么旨在破坏T1DM潜在的自身免疫过程的策略可能会逆转这种疾病。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，成年人的胰腺保持着不断产生新的β细胞的能力。由于过去半个世纪以来大气中碳- 14水平的变化（核试验之后）已经被精确地追踪到了，因此组织DNA中碳- 14的含量可以用来量化DNA的年龄（即DNA产生的时间），从而量化组织内细胞的周转率。例如，DNA内的AMS 14C测量显示了人类大脑中惊人的细胞周转率。我们试图通过应用AMS技术测量尸体供体β细胞DNA中的14C来验证我们的假设，即β细胞也在“翻转”。不同年龄的人β细胞中14C的AMS测量应该使我们能够回答β细胞是否在成人中再生。数据表明β细胞在成人胰腺中再生，这将促进旨在进一步促进这一过程的研究，并将促使人们努力识别新β细胞的祖细胞。或者，如果我们没有发现证据表明新的β细胞是在成年期产生的，那么我们更应该努力寻找胰岛素产生细胞的新来源（如胚胎干细胞、细胞治疗等）。

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.).