Role of Abcg2/Bcrp1 in Cardiac Side Population Cells

Abcg2/Bcrp1 在心侧细胞群中的作用

• 批准号: 7663968
• 负责人: Ronglih Liao
• 金额: $ 42.25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663968
• 关键词: 5' Untranslated Regions; ATP-Binding Cassette Transporters; Abbreviations; Address; Adult; Affect; Apoptotic; Binding; Biochemical; Biological Process; Biology; Bone Marrow; Bone Marrow Transplantation; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Characteristics; Chronic; Coupling; Data; Development; Dyes; Endothelial Cells; Environment; Exhibits; Exons; Family; Fluorescence-Activated Cell Sorting; Functional disorder; Goals; Green Fluorescent Proteins; Growth; Heart; Heart failure; Hematopoiesis; Hematopoietic stem cells; Hospitalization; Hypoxia; Hypoxia Inducible Factor; In Vitro; Incidence; Injury; Internal Ribosome Entry Site; Intervention; Knock-out; Laboratories; Life; Mediating; Membrane; Messenger RNA; Methodology; Molecular; Molecular Target; Multi-Drug Resistance; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Necrosis; Neonatal; Newly Diagnosed; Nucleotides; Null Lymphocytes; P-Glycoprotein; P-Glycoproteins; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; RNA Splicing; Regulation; Reporter; Resistance; Role; Side; Site; Stem cells; Stimulus; System; Testing; Therapeutic; Undifferentiated; Variant; Ventricular Remodeling; Work; cell type; functional loss; human ABCG2 protein; in vivo; insight; interdisciplinary approach; loss of function; malignant breast neoplasm; member; mouse model; novel; prevent; promoter; protective effect; public health relevance; repaired; research study; response; stem

DESCRIPTION (provided by applicant): Chronic heart failure is the leading cause for hospitalization in the US, affecting over five million patients, with over a half million newly diagnosed cases each year. Current therapies do not address the central pathophysiology underlying the development of heart failure, namely, the loss of functional cardiomyocytes. Therefore, cardiac progenitor cells hold enormous potential for therapeutic cardiac repair and regeneration. We and others have recently confirmed the existence of one such progenitor cell population in adult murine myocardium. These so-termed cardiac side population (CSP) cells are identified in adult hearts by their distinct Hoechst 33342 dye extrusion properties, and represent a distinct progenitor cell population. While in-vitro these CSP cells are capable of both biochemical and more importantly, functional cardiomyogenic differentiation, in- vivo such differentiation occurs at an exceedingly limited rate, and is limited by the mechanisms regulating cellular survival, proliferation and differentiation. CSP cells express a unique set of ATP binding cassette (ABC) transporters, including the breast cancer resistant protein (Abcg2/Bcrp1). While these ABC transporters confer the Hoechst dye efflux properties characteristic of SP cells, emerging evidence has also suggested that members of the ABC transporter family may serve as a conduit for the interaction of stem cells with their local environment, thereby mediating the intricate regulation of progenitor cell fate and function in response to external and internal stimuli. Indeed, our preliminary data demonstrate that Abcg2/Bcrp1 expression is gradually down- regulated during the first few weeks of post-natal development and is sharply up-regulated again in response to cardiac injury, in close correlation with CSP proliferation capacity. Furthermore, through gain and loss of function experiments, our data also demonstrate that the dynamic expression of Abcg2/Bcrp1 plays a critical role in the protection and functional regulation of CSP cells in both normal myocardium and following injury. Little is known about the control of dynamic Abcg2/Bcrp1 expression and its subsequent regulation of CSP proliferation and function. Thus, utilizing a multidisciplinary approach of in-vitro and in-vivo methodologies, here, we propose to determine (a) the molecular mechanism(s) controlling Abcg2/Bcrp1 expression and (b) the role of Abcg2/Bcrp1 in regulating the biological function of cardiac SP cells during post-natal development and following injury. Data obtained from this application will provide the first insight into the role of ABCG2/Bcrp1 in cardiac progenitor cells as well as provide novel molecular targets for enhancing therapeutic cardiac regeneration. PUBLIC HEALTH RELEVANCE Cardiovascular disease remains the single greatest cause of death in the Westernized world, claiming more lives in the US than the four next leading causes, combined. Among cardiovascular disease, the incidence of heart failure continues to rise at a staggering rate. Recent identification of the existence of cardiac stem/progenitor cells highlights the therapeutic potential of using these cells in cardiac repair and regeneration. However, our limited understanding of the biology of these cardiac progenitor cells and the regulation of their proliferation and differentiation prevents us from realizing the full potential of such intervention. The results obtained from our proposal will fill this gap and contribute to our understanding of molecular regulation of these cardiac progenitor cells.

描述（由申请人提供）：慢性心力衰竭是美国住院的主要原因，影响超过 500 万患者，每年新诊断病例超过 50 万。目前的疗法并未解决心力衰竭发展的核心病理生理学问题，即功能性心肌细胞的丧失。因此，心脏祖细胞在治疗性心脏修复和再生方面具有巨大的潜力。我们和其他人最近证实了成年小鼠心肌中存在一种这样的祖细胞群。这些所谓的心脏侧群 (CSP) 细胞在成人心脏中通过其独特的 Hoechst 33342 染料挤出特性进行鉴定，并代表了独特的祖细胞群。虽然在体外这些CSP细胞能够进行生化分化，更重要的是能够进行功能性心肌形成分化，但在体内这种分化发生的速度极其有限，并且受到调节细胞存活、增殖和分化的机制的限制。 CSP 细胞表达一组独特的 ATP 结合盒 (ABC) 转运蛋白，包括乳腺癌抗性蛋白 (Abcg2/Bcrp1)。虽然这些 ABC 转运蛋白赋予 SP 细胞特有的 Hoechst 染料流出特性，但新出现的证据也表明 ABC 转运蛋白家族的成员可能作为干细胞与其局部环境相互作用的管道，从而介导祖细胞的复杂调节。细胞命运和功能响应外部和内部刺激。事实上，我们的初步数据表明，Abcg2/Bcrp1 表达在出生后发育的最初几周内逐渐下调，并在心脏损伤后再次急剧上调，与 CSP 增殖能力密切相关。此外，通过功能获得和丧失实验，我们的数据还表明Abcg2/Bcrp1的动态表达在正常心肌和损伤后CSP细胞的保护和功能调节中发挥着关键作用。关于动态 Abcg2/Bcrp1 表达的控制及其对 CSP 增殖和功能的后续调节知之甚少。因此，利用体外和体内方法学的多学科方法，在这里，我们建议确定（a）控制 Abcg2/Bcrp1 表达的分子机制和（b）Abcg2/Bcrp1 在调节生物体内的作用。心脏 SP 细胞在产后发育和损伤后的功能。从该应用中获得的数据将首次深入了解 ABCG2/Bcrp1 在心脏祖细胞中的作用，并为增强治疗性心脏再生提供新的分子靶点。公共卫生相关性 心血管疾病仍然是西方世界中最大的单一死因，在美国夺去的生命比紧随其后的四种主要原因的总和还多。在心血管疾病中，心力衰竭的发病率持续以惊人的速度上升。最近对心脏干/祖细胞存在的鉴定突出了使用这些细胞在心脏修复和再生中的治疗潜力。然而，我们对这些心脏祖细胞的生物学及其增殖和分化的调节的有限了解使我们无法充分发挥这种干预的潜力。从我们的提案中获得的结果将填补这一空白，并有助于我们了解这些心脏祖细胞的分子调节。