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.

人珠蛋白基因的个体发生是研究的重要焦点，这不仅是关于控制该复杂基因系统表达的基础发育生物学和分子遗传学，而且还因为修饰该发育控制将在治疗血红蛋白的流行遗传疾病（例如镰状细胞性贫血和地中海贫血）中具有治疗价值。这是我们25年来的研究重点之一。 在其他研究结果中，我们证明了现在被批准通过提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，特别是改变环GMP水平。 这些结果将我们的NO（见年度报告DK 025093和DK 025104）和我们的镰状细胞工作结合在一起，并使我们继续在合作研究中进行人类造血细胞的基因表达研究。一项这样的研究表明，许多转录因子在培养的人CD 34+红系细胞的个体发育过程中发生变化，特别是与JAK-STAT和AKT途径相关。在随后的研究中，我们发现与其他造血细胞相比，CD 34+细胞具有与mTOR信号传导途径相关的PI 3/AKT和MAPK基因的基因表达水平增加。 我们还使用了骨髓增殖细胞-羟基脲研究的主要焦点-来显示多种血管生成相关基因受到这种药物治疗的影响。最近，这些研究表明，由羟基脲产生的一氧化氮（NO）以及由一氧化氮合酶（NOS）酶增加的NO合成有助于这种药物的作用。 我们对理解镰状细胞患者疼痛表型的长期兴趣已经导致分析表明，疼痛的感知既有中枢神经系统方面，也有外周神经系统方面。 我们还表明，通过羟基脲升高Hb F可降低镰状细胞疼痛，如这些研究中使用外部探针所测量的。重要的是，我们的数据表明，中枢对疼痛的敏感性是这些患者疼痛的重要组成部分，并受到胎儿血红蛋白水平的影响。我们还分析了镰状细胞患者前臂和心肌血流的对比增强超声灌注成像的数据，发现当校正贫血程度时，羟基脲（hydroxycarbamide）增加了两个器官的血流，肌肉血流与胎儿血红蛋白水平相关。 最近的研究集中在开发镰状细胞病的新疗法。 我们正在与NIH（NHLBI）镰状细胞项目的成员进行几项研究。 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）治疗患者的效果，以观察总血红蛋白水平的增加是否对上述疾病表现有有益影响。我们也回到了我们以前的MCellthe镰状细胞法，测定这些患者的NO代谢物水平和无细胞血红蛋白水平，希望招募更大的队列，以更好地衡量亚硝酸盐给药的潜在价值。我们还与NIH疟疾小组合作，以了解脑型疟疾的机制，并正在评估这种情况下NO的产生和破坏以及α珠蛋白基因数量变化的影响，在其他研究中，我们正在合作研究这种疾病的血栓形成过程，特别是NO对血液凝固的影响。 我们继续与NIH历史办公室合作，将NIH科学史存档，回顾口述历史，组织会议和讲座，以及编辑相关主题的研讨会，特别是多年来在“生物学和医学展望”杂志上发表。“我们组织了几次关于NIH最近历史的研讨会，其中一次是与NIH研究节一起举办的。最近，我们帮助NIH开发了一个关于C. B.安芬森，该实验室（分支）的前负责人，这是伴随着一个专题讨论会，致力于他的职业生涯。 与NIH历史办公室代理主任Christopher Wanjek先生一起，我们组织了一系列每月的生物医学历史讲座，供国际发行（和存档）。在过去的一年里，一位新的NIH历史学家被任命，我们已经开始与她（Kim Pelis博士）和NIH历史办公室的其他工作人员合作，重新建立更多的项目，这些项目在过去的半个世纪里对这项活动至关重要。 我们最近发表了一篇关于镰状血红蛋白在该病发病机制中的细胞内聚合的长篇综述，重点是历史方面，并与Noguchi和Kim-Shapiro博士共同撰写;这篇文章发表在由M.T. Gladwin，G.J. Kato和E.M. Novelli，由McGraw-Hill于2021年出版。