Bone Marrow Microenvironmental Expression of Cytochrome P450 Enzymes

细胞色素 P450 酶的骨髓微环境表达

• 批准号: 8869404
• 负责人: Gabriel Ghiaur
• 金额: $ 13.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869404
• 关键词: Accounting; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Affect; Area; Biological; Biological Availability; Blood; Bone Marrow; Bypass; CYP26B1 gene; CYP3A4 gene; Cell physiology; Cells; Chemicals; Clinical; Clinical Research; Cues; Cytochrome P450; Data; Diagnosis; Differentiation Therapy; Disease; Disease remission; Drug resistance; Elements; Enzymes; Equilibrium; Faculty; Failure; Fellowship; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhage; Hepatic; Homeostasis; Human; In Vitro; Infection; Inflammation; Inflammatory; Isoenzymes; Knock-out; Knowledge; Laboratories; Laboratory Research; Malignant - descriptor; Mediating; Medicine; Mesenchymal; Metabolism; Methods; Modeling; Monitor; Mus; Nature; Outcome; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Physicians; Physiological; Play; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Process; Property; Psoriasis; Publishing; Radiation therapy; Recovery; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Resistance; Retinoids; Role; Sampling; Scientist; Signal Transduction; Stem cells; Stress; Time; Training Programs; Translating; Translations; Tretinoin; Universities; Vitamin A; base; cancer cell; cancer stem cell; career; cell behavior; chemotherapy; clinical application; design; drug metabolism; graduate student; improved; inhibitor/antagonist; instructor; leukemia treatment; leukemic stem cell; mouse model; novel; oncology; professor; public health relevance; response; retinaldehyde dehydrogenase; retinoic acid 4-hydroxylase; skills; small hairpin RNA; stem cell differentiation; stem cell niche; tool

 DESCRIPTION (provided by applicant): This proposal describes a research plan into the role of bone marrow microenvironment in modulating retinoid homeostasis with implications for both normal as well as malignant hematopoiesis and a training program to develop the principal investigator, Dr. Gabriel Ghiaur from a junior faculty into an independent physician-scientist. Dr. Ghiaur studied normal hematopoiesis as a graduate student in the laboratory of Dr. David Williams and then as a post-doctoral fellow in the laboratory of Dr. Jose Cancelas at Cincinnati Children's Hospital. As a hematology fellow in the laboratory of Dr. Richard Jones, Johns Hopkins University, he focused on the role of retinoic acid (RA) in hematopoiesis. Dr. Jones was the first investigator to identify retinaldehyde dehydrogenase as a marker of normal and malignant hematopoietic stem cell and is a recognized expert in the field. Upon completion of his clinical and research fellowship, Dr. Ghiaur has joined the Hematological Malignancies division, at Johns Hopkins in July 2013 as an Instructor and was recently promoted to Assistant Professor of Oncology and Medicine. This laboratory based tenure track position assure Dr. Ghiaur 80% protected time for research and this grant will support his goal of pursuing a career as a laboratory based translational researcher in hematologic malignancies. Regulation of hematopoietic stem cell (HSC) function during steady state conditions as well as during disease states is an area of intense research. Multiple cell-intrinsic and environmental cues have been proposed to connect physiological needs and stem cell behavior. Studies comparing HSC with their more committed progenitor cells, revealed RA as a potential regulator of HSC function. To this end, HSCs appear posed to differentiate if not protected by a RA-low niche maintained via stromal expression of CYP26, a RA- metabolizing enzyme. Thus, modulations of CYP26 expression by inflammatory signals for instance could change RA levels in the niche and thus, adjust HSC behavior to respond to hematological stress. More so, since RA therapies have revolutionized the treatment of acute promyelocytic leukemia but unfortunately had no impact on other hematological malignancies, tempering with stromal CYP protective mechanisms could expand the clinical applications of differentiation therapies. A better understanding of niche drug metabolizing properties and how they change during hematological stress and during therapy is needed to before the develop CYP inhibitors as clinical tools in hematology. The overarching hypothesis of the proposed research is that P450 enzymes expressed by various hematopoietic microenvironments create drug-free sanctuaries in the bone marrow and modulate HSC homeostasis as well as chemotherapy resistance. This proposal aims to: 1) Determine how the bone marrow niche controls RA bioavailability to modify HSC behavior; specifically what stem cell niche (endothelial, mesenchymal or endosteal) depends on CYP26 activity to maintain human HSC, how the local (niche) control of RA levels compares to systemic (hepatic) metabolism and how RA metabolism changes during hematological stress. 2) Study the effects of stromal cytochrome P450 on drug resistance, initially as it relates to resistance RA therapy and then as it relates to chemotherapy in general. The investigators hypothesize that a sophisticated understanding of local drug metabolism will aid in designing optimal strategies to bypass the chemical barriers posed by stromal drug metabolizing enzymes and thus, opening the malignant stem cell niche to systemic chemotherapy.

 描述（由申请人提供）：本提案描述了一项研究计划，研究骨髓微环境在调节类维生素A稳态中的作用，对正常和恶性造血都有影响，并描述了一项培训计划，旨在将主要研究者Gabriel Ghiaur博士从初级教师培养成独立的医生-科学家。博士 Ghiaur在大卫威廉姆斯博士的实验室研究正常造血，然后在辛辛那提儿童医院的Jose Cancelas博士的实验室担任博士后研究员。作为约翰霍普金斯大学理查德·琼斯博士实验室的血液学研究员，他专注于维甲酸（RA）在造血中的作用。Jones博士是第一个将视黄醇脱氢酶鉴定为正常和恶性造血干细胞标志物的研究者，是该领域公认的专家。在完成临床和研究奖学金后，Ghiaur博士于2013年7月加入约翰霍普金斯的血液肿瘤部门担任讲师，最近晋升为肿瘤学和医学助理教授。这个基于实验室的终身职位保证Ghiaur博士80%的研究时间受到保护，这笔赠款将支持他作为血液恶性肿瘤实验室转化研究员的职业目标。 造血干细胞（HSC）功能在稳态条件下以及在疾病状态下的调节是一个深入研究的领域。已经提出了多种细胞内在和环境线索来连接生理需求和干细胞行为。比较HSC与其更定向的祖细胞的研究揭示了RA作为HSC功能的潜在调节剂。为此，如果不受经由CYP 26（一种RA代谢酶）的基质表达维持的RA低生态位的保护，HSC似乎倾向于分化。因此，通过炎症信号调节CYP 26表达例如可以改变小生境中的RA水平，从而调节HSC行为以响应血液学应激。更重要的是，由于RA疗法已经彻底改变了急性早幼粒细胞白血病的治疗，但不幸的是对其他血液恶性肿瘤没有影响，因此调节基质细胞保护机制可以扩大分化疗法的临床应用。更好地了解利基药物 代谢特性以及它们在血液学应激期间和治疗期间如何变化是在开发作为血液学临床工具的β-内酰胺酶抑制剂之前所需要的。 这项研究的总体假设是，由各种造血微环境表达的P450酶在骨髓中创造了无药物的避难所，并调节HSC的稳态以及化疗耐药性。该提案旨在：1）确定骨髓生态位如何控制RA生物利用度以改变HSC行为;具体地，什么样的干细胞生态位（内皮细胞、间充质细胞或骨内膜细胞）依赖于CYP 26活性来维持人HSC，RA水平的局部（生态位）控制与全身（肝）代谢相比如何以及RA代谢在血液应激期间如何变化。2)研究间质细胞色素P450对耐药性的影响，最初是因为它与耐药性RA治疗有关，然后是因为它与一般化疗有关。研究人员假设，对局部药物代谢的复杂理解将有助于设计最佳策略，以绕过基质药物代谢酶造成的化学屏障，从而为全身化疗打开恶性干细胞的小生境。