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. For nearly 4 decades, the human heart has been considered a post-mitotic organ composed of a predetermined number of myocytes, which is established at the end of gestation. According to this Old Paradigm, the generation of myocytes ceases at birth and their number is preserved throughout life until death of the organ and organism. Cardiac growth postnatally and organ hypertrophy in the adult occur only by myocyte enlargement. On this premise, the age of myocytes corresponds to the age of the organ and organism, i.e., cellular, organ and organism age coincide. Recent results from our laboratory and others have documented that tissue specific stem cells reside in the human heart. Human cardiac stem cells (hCSCs) are self-renewing and multipotent in vitro and in vivo;hCSCs differentiate in myocytes, and vascular smooth muscle cells (SMCs) and endothelial cells (ECs) organized in coronary vessels. The recognition that the human heart possesses a stem cell compartment has imposed a reevaluation of cardiac homeostasis, aging and pathology. The New Paradigm refutes the conviction that myocytes are formed only during embryonic development and suggests that the replacement of coronary vascular SMCs and ECs is regulated by differentiation of hCSCs rather than by the ability of these mature cells to divide. A novel conceptual framework of the heart has emerged;the Heart Is a Self-renewing Organ characterized by a compartment of resident stem cells. This discovery has laid the ground work for the use of hCSCs in the treatment of the failing heart. Currently, two phase I clinical trials are in progress (ClinicalTrials.gov Identifier: NCT00474461;Identifier: NCT00893360). Our understanding of the cellular processes implicated in the maturation, homeostasis and repair of the human heart is extremely deficient and the need for basic information is striking. Findings in nematodes, fruit flies, zebra fish and rodents have often been translated to human beings with little caution, emphasizing the necessity to study the fundamental principles that regulate the plasticity of the myocardium during the lifespan of women and men. Moreover, the mechanisms modulating the response of the female and male heart to ischemic and non-ischemic myocardial injury and the principal factors conditioning end-stage heart failure and death in humans are at present unknown. Thus, the major objective of this application is to establish the rate of myocyte and non-myocyte turnover mediated by hCSC activation and differentiation in the developing, adult, aging and failing heart. To achieve this goal, we will employ retrospective 14C birth dating of cardiac cells to establish the average age of myocytes and non-myocytes. This information will be complemented by defining the age distribution of myocytes and non-myocytes utilizing a mathematical model of age-structured cell populations. These data will offer a novel comprehensive perspective of the cellular processes which govern the lifespan of the human heart. This information is critical for the recognition of the mechanisms that control the dynamics of the human heart, its growth reserve, adaptation to stress and failure.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR013461-13
Application #
8362769
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
$23,405
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

Showing the most recent 10 out of 123 publications