Control Of Human Hemoglobin Gene Expression and Approaches to the Therapy of Sickle Cell Disease

人类血红蛋白基因表达的控制和镰状细胞病的治疗方法

• 批准号: 10700661
• 负责人: Alan Schechter
• 金额: $ 12.9万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700661
• 关键词: Adhesions; Affect; Anabolism; Anemia; Annual Reports; Archives; Biology; Blood Circulation; Blood coagulation; Blood flow; CD34 gene; Cells; Cerebral Malaria; Characteristics; Clinical Research; Collection; Complex; Cyclic GMP; Data; Data Analyses; Development; Developmental Biology; Disease; Drug usage; Enzymes; Erythroid; Erythroid Cells; Erythropoietin; Exhibits; Fees; Festival; Fetal Hemoglobin; Forearm; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Diseases; Globin; Growth; Head; Hematopoietic; Hemoglobin; Hemoglobin concentration result; Hemolysis; Historical Aspects; Human; Impairment; Institution; International; Intramural Research Program; Ions; Journals; Laboratories; Lead; Life; MAP Kinase Gene; Malaria; Measures; Medicine; Metabolism; Modality; Molecular Genetics; Multicenter Studies; Muscle; Myeloproliferative disease; Myocardial; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Oral; Organ; PI3 gene; Pain; Pathogenesis; Pathway interactions; Patients; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacology; Phenotype; Polymers; Positioning Attribute; Process; Production; Proto-Oncogene Proteins c-akt; Publications; Publishing; Recording of previous events; Reporting; Research; Reticulocyte count; Science; Series; Severity of illness; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Signal Transduction; Syndrome; System; Textbooks; Thalassemia; Therapeutic; Thrombosis; United States National Institutes of Health; Universities; Variant; Work; alpha Globin; alpha-Thalassemia; biophysical analysis; career; central sensitization; clinical center; clinical effect; cohort; contrast enhanced; gamma Globin; hydroxyurea; improved; interest; lectures; mTOR Signaling Pathway; meetings; member; novel strategies; novel therapeutics; pain perception; pandemic disease; perfusion imaging; polymerization; programs; recruit; sickling; skeletal; symposium; thrombotic; transcription factor; treatment effect; treatment response; ultrasound

The ontogeny of the human globin genes is an important focus of study both with respect to the fundamental developmental biology and molecular genetics of the control of expression of this complex gene system, but also because modifying this developmental control would be of therapeutic value in the treatment of the prevalent genetic diseases of hemoglobin, such as sickle cell anemia and thalassemia. This has been one of our research emphases for more than 25 years. Among other findings was our demonstration that hydroxyurea, now approved to treat sickle cell anemia by elevating fetal hemoglobin, affects intracellular nitric oxide metabolism, specifically changing cyclic GMP levels. These results brought together our NO (see Annual Reports DK025093 and DK025104) and our sickle cell work and has led us to continue gene expression studies in human hematopoietic cells in collaborative studies. One such study shows that many transcription factors change during ontogeny of human CD34+ erythroid cells in culture, especially related to the JAK-STAT and AKT pathways. In subsequent studies we showed that CD 34+ cells have increased levels of gene expression of the PI3/AKT and MAPK genes related to the mTOR signaling pathways as compared to other hematopoietic cells. We have also used myeloproliferative cells -the main focus of hydroxyurea studies - to show that a variety of angiogenic-related genes are affected by treatment with this agent. More recently these studies have shown that nitric oxide (NO) produced by hydroxyurea, as well as increased synthesis of NO by nitric oxide synthase (NOS) enzymes contribute to the effects of this drug. Our long interest in understanding the pain phenotype in sickle cell patients has resulted in analyses which suggest that there are both central and peripheral nervous system aspects to perception of pain. We have also shown that elevation of Hb F by hydroxyurea decreases sickle cell pain as measured in these studies with external probes. Importantly our data showed that central sensitization to pain is an important component of pain in these patients and is affected by fetal hemoglobin levels. We have also analyzed data from contrast-enhanced ultrasound perfusion imaging of forearm and myocardial blood flow in sickle cell patients and have found that when corrected for degree of anemia hydroxyurea (hydroxycarbamide) increases blood flow in both or organs and muscle blood flow correlates with fetal hemoglobin levels. More recent studies are focused on developing new therapies for sickle cell disease. We are working with members of the sickle cell program of NIH (NHLBI) on several studies. In particular we are planning to evaluate the effects of treatment of patients with erythropoietin and other erythroid stimulating agents (ESAs) to see if increases in total hemoglobin levels have beneficial effects on disease manifestations as described above. We have also returned to our previous mcellthe sickle easurements of NO metabolite levels and of cell-free hemoglobin in these patients, hoping to recruit a larger cohort, to better gauge the potential value of nitrite administration. We are also working with an NIH malaria group to understand the mechanism of cerebral malaria and are evaluating the production and destruction of NO in this condition as well as the effects of variations in alpha globin gene numbers and in other studies we are collaborating on studies of thrombotic processes in this disease, with special reference to the effects of NO on blood clotting. We continue working with the NIH Office of History in archiving NIH science history, reviewing oral histories, and organizing meetings and lectures, as well as editing symposia on related topics for publication, particularly over many years in the journal "Perspectives in Biology and Medicine." We organized several symposia on the recent history of NIH, one of which was presented in conjunction with the NIH Research Festival. We more recently helped develop an exhibit for NIH on the life and work of C.B. Anfinsen, the former head of this Laboratory (Branch), which was accompanied by a symposium devoted to his career. With Mr. Christopher Wanjek, the acting director of the NIH History Office, we have organized a monthly series of biomedical history lectures for international distribution (and archiving) on Zoom). In the last year a new NIH Historian has been appointed and we have begun to work with her (Dr. Kim Pelis) and the other staff of the NIH History Office to re-establish more of the programs that have been essential to this activity over the last half-century. We have recently published a long review of the intracellular polymerization of sickle hemoglobin in the pathogenesis of this disease, with emphasis on historical aspects and written with Drs. Noguchi and Kim-Shapiro; this article appeared in the textbook Sickle Cell Disease, edited by M.T. Gladwin, G.J. Kato, and E.M. Novelli, published in 2021 by McGraw-Hill.

人类球蛋白基因的个体发育是研究这种复杂基因系统表达的基本发育生物学和分子遗传学的重要重点，而且还因为修改这种发育控制在治疗流行的遗传性遗传疾病的治疗是具有治疗价值的，例如诸如小心细胞和thalsamia的流行遗传疾病。 25年来，这一直是我们的研究重点之一。 除其他发现外，我们的证明是，现在批准通过升高胎儿血红蛋白来治疗镰状细胞贫血的羟基脲会影响细胞内一氧化氮代谢，特别改变了环状GMP水平。 这些结果汇集了我们的NO（请参阅年度报告DK025093和DK025104）和我们的镰状细胞工作，并使我们在协作研究中继续在人类造血细胞中继续基因表达研究。一项这样的研究表明，在培养中人类CD34+红细胞的个体发育过程中，许多转录因子在培养中发生了变化，尤其是与JAK-STAT和AKT途径有关的。在随后的研究中，我们表明，与其他造血细胞相比，CD 34+细胞具有与MTOR信号通路相关的PI3/AKT和MAPK基因的基因表达水平增加。 我们还使用了脊髓增生性细胞（羟基脲研究的主要重点）来表明，多种与血管生成相关的基因受该药物治疗的影响。最近，这些研究表明，羟基脲产生的一氧化氮（NO），以及一氧化氮合酶（NOS）酶增加NO的合成，从而有助于该药物的作用。 我们对了解镰状细胞患者的疼痛表型的长期兴趣导致了分析，这表明疼痛感知既有中心和周围神经系统方面。 我们还表明，通过外部探针在这些研究中测量的羟基脲升高会减轻镰状细胞疼痛。重要的是，我们的数据表明，中央对疼痛的敏感是这些患者疼痛的重要组成部分，并且受胎儿血红蛋白水平的影响。我们还分析了镰状细胞患者的前臂和心肌血流的对比增强的超声灌注成像的数据，并发现，当校正羟基酸贫血程度时，羟基酸贫血（羟基甲酰胺）（羟基甲酰胺）会增加或器官和肌肉血液流动中的血液流量与fetal血液流动相关。 最近的研究集中在开发用于镰状细胞疾病的新疗法上。 我们正在与NIH（NHLBI）的镰状细胞计划成员合作进行多项研究。 特别是我们计划评估促红细胞生成素和其他红细胞刺激剂（ESA）的治疗的影响，以查看总血红蛋白水平的升高是否对上述疾病表现有益影响。在这些患者中，我们还回到了以前的Mcellthe镰刀上的NO NO代谢物水平和无细胞血红蛋白的疾病，希望招募更大的队列，以更好地评估亚硝酸盐给药的潜在价值。我们还与NIH疟疾组合作了解脑疟疾的机制，并评估了这种情况下NO的产生和破坏以及Alpha Glopin基因数量的变化的影响，在其他研究中，我们正在协作对这种疾病中的血栓形成过程的研究，并特别参考了NO对血液凝结的影响。 我们将继续与NIH历史办公室合作，以归档NIH科学史，审查口述历史，组织会议和讲座，以及编辑有关发表相关主题的研讨会，尤其是多年来在“生物学和医学的观点”中。 我们在NIH的近期历史上组织了几次研讨会，其中之一是与NIH研究节一起提出的。我们最近帮助开发了NIH的展览，内容涉及该实验室（分支机构）的前负责人C.B. Anfinsen的生活和工作，该展览伴随着致力于他职业生涯的研讨会。 与NIH历史办公室的代理总监Christopher Wanjek先生一起，我们在Zoom上组织了每月一系列的生物医学历史讲座，以进行国际分销（和归档））。去年，任命了一位新的NIH历史学家，我们开始与她（Kim Pelis博士）和NIH历史办公室的其他工作人员合作，以重新建立更多对过去半个世纪至关重要的计划。 我们最近发表了对镰状血红蛋白在这种疾病发病机理中的细胞内聚合的长期综述，重点是历史方面，并用DRS书写。 Noguchi和Kim-Shapiro；本文出现在M.T.编辑的教科书镰状细胞病中。 Gladwin，G.J。麦格劳 - 希尔（McGraw-Hill）于2021年出版，加托（Kato）和E.M. Novelli。