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.).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR013461-13
Application #
8362759
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
2011-06-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
13
Fiscal Year
2011
Total Cost
$46,810
Indirect Cost
Name
Lawrence Livermore National Laboratory
Department
Biology
Type
Organized Research Units
DUNS #
827171463
City
Livermore
State
CA
Country
United States
Zip Code
94550
Wan, Debin; Yang, Jun; Barnych, Bogdan et al. (2017) A new sensitive LC/MS/MS analysis of vitamin D metabolites using a click derivatization reagent, 2-nitrosopyridine. J Lipid Res 58:798-808
Stornetta, Alessia; Zimmermann, Maike; Cimino, George D et al. (2017) DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine. Chem Res Toxicol 30:388-409
Wang, Si-Si; Zimmermann, Maike; Zhang, Hongyong et al. (2017) A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer. Int J Cancer 141:604-613
Wang, Zhican; Fang, Ying; Teague, Juli et al. (2017) In Vitro Metabolism of Oprozomib, an Oral Proteasome Inhibitor: Role of Epoxide Hydrolases and Cytochrome P450s. Drug Metab Dispos 45:712-720
Kim, Jeffrey; Stewart, Benjamin; Weiss, Robert H (2016) Extraction and Quantification of Tryptophan and Kynurenine from Cultured Cells and Media Using a High Performance Liquid Chromatography (HPLC) System Equipped with an Ultra-Sensitive Diode Array Detector. Bio Protoc 6:
Pan, Amy; Zhang, Hongyong; Li, Yuanpei et al. (2016) Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer. Nanotechnology 27:425103
Wang, Sisi; Zhang, Hongyong; Scharadin, Tiffany M et al. (2016) Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer. PLoS One 11:e0146256
McCartt, A D; Ognibene, T; Bench, G et al. (2015) Measurements of Carbon-14 With Cavity Ring-Down Spectroscopy. Nucl Instrum Methods Phys Res B 361:277-280
Cai, Hong; Scott, Edwina; Kholghi, Abeer et al. (2015) Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Sci Transl Med 7:298ra117
Tomlinson, Ben; Lin, Tzu-yin; Dall'Era, Marc et al. (2015) Nanotechnology in bladder cancer: current state of development and clinical practice. Nanomedicine (Lond) 10:1189-201

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