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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 I型糖尿病(T1 DM)是由免疫介导的胰岛细胞群中产生胰岛素的胰岛细胞(β细胞)的破坏引起的。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，这就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是非常困难的，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。这些并发症包括肾功能衰竭、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一项重要的治疗进展。其他研究人员正在尝试开发另一种产生胰岛素的细胞来源。然而，尽管这个问题非常重要，但成人胰腺是否能再生β细胞仍是个未知数。例如，如果在出生后或成年后有可能出现显著的β细胞再生，那么旨在扰乱T1糖尿病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人胰腺干细胞存在的观点，并将支持对此类干细胞的搜索。我们的假设是，成人胰腺保持不断产生新的β细胞的能力。由于已经准确跟踪了过去半个世纪大气中14C水平的变化(核试验的次要影响)，组织DNA中包含的14C可以用来量化DNA的年龄(即DNA制造的时间)，从而确定该组织内细胞的周转率。例如，这项DNA中的AMS 14C测量显示，人类大脑中的细胞周转率令人惊讶。我们试图通过应用AMS技术测量身体捐赠者的β细胞DNA中的14C来检验我们的假设，即β细胞也在“翻转”。AMS对不同年龄的人的β细胞中14C的测量应该使我们能够回答成年人类的β细胞是否会再生。数据表明，在成人胰腺中再生的β细胞将促进旨在进一步促进这一过程的研究，并将刺激为新的β细胞识别祖细胞的努力。或者，如果我们发现没有证据表明成年后会产生新的β细胞，那么更合适的做法是为胰岛素产生细胞寻找新的来源(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. 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.).