Acute Anemia of Inflammation: Mechanisms and Novel Therapies

 描述（由申请人提供）：Dr. Airie Kim是一名肺部和重症监护医生，对重症监护室（ICU）中脓毒症和严重炎症的病理生理学非常感兴趣。这个问题的一个方面是特别适合实验室研究的炎症性贫血（AI），这是一种与发病率和死亡率密切相关的流行疾病。她的长期目标是成为AI领域的专家和学术领导者，最终在其他炎症相关的重症方面，她将得到她的主要导师Tomas Ganz博士的支持，Tomas Ganz博士是贫血和铁代谢领域的领导者，还有她的同事导师和顾问，他们将提供多学科的专业知识，在造血的理论和技术方面培训金博士，炎症通过加州大学洛杉矶分校的临床和转化科学研究所（CTSI），金博士将有机会参加众多职业发展研讨会，这些研讨会涉及资助写作、手稿准备和伦理研究等主题。她还将参加研究生课程，以获得免疫学，药理学，造血和生物统计学的进一步培训。金博士很幸运，她的机构的全力支持，以及在加州大学洛杉矶分校，一个著名的研究中心进行她的研究项目的人的优势。该提案概述了一个为期5年的研究和职业发展计划，该计划将使Kim博士成为一名从事高水平科学研究的独立医生科学家。该项目旨在阐明急性和严重AI的机制，并在小鼠模型中测试新疗法及其作用机制。Kim博士最近描述了由热灭活的流产布鲁氏菌（BA）诱导的AI小鼠模型，该模型模拟了人类ICU贫血的特征，包括快速发作，尽管保留了铁储存，但仍存在低铁血症，红细胞寿命缩短和红细胞生成抑制。使用AI的BA小鼠模型，Specific Aim 1a旨在全面研究潜在机制，包括促红细胞生成素（EPO）产生减少、EPO受体活性降低和红细胞生成分化改变的潜在贡献。与AI发展有关的一种特异性炎性细胞因子是干扰素-γ（IFN-γ）。使用IFN-γR1-/-小鼠，Specific Aim 1b旨在检查IFN-γ参与红系祖细胞分化、巨噬细胞活化和红细胞寿命的机制。治疗AI的两种有希望的候选药物是口服生物可利用的脯氨酰羟化酶（PHD）抑制剂，已被证明可以改善慢性肾功能衰竭患者的贫血，以及erythroferrone（ERFE），这是Kim博士的小组新发现的一种激素，由EPO诱导并抑制hepcidin表达。对于特定目标2a，Kim博士将在BA小鼠模型中测试PHD抑制剂，以研究其在急性和重度炎性贫血中的机制和潜在治疗作用。对于特定目的2b，Kim博士将在BA小鼠模型中使用鼠重组ERFE，以研究对急性和重度AI中红细胞生成和恢复的影响。该项目旨在回答有关人工智能的重要机械问题，并研究新疗法的使用。通过这项工作，Kim博士旨在提高我们对ICU贫血常见但知之甚少的疾病的认识和潜在治疗方法。

 DESCRIPTION (provided by applicant): Dr. Airie Kim is a Pulmonary and Critical Care physician who is greatly interested in the pathophysiology of sepsis and overwhelming inflammation in intensive care units (ICUs). One facet of this problem that is particularly amenable to laboratory study is anemia of inflammation (AI), a prevalent condition with strongly associated morbidities and mortality. Her long-term goal is to become an expert and academic leader in the field of AI, and eventually in other inflammation-related aspects of critical illness She will be supported by her primary mentor, Dr. Tomas Ganz, a leader in the field of anemia and iron metabolism, as well as her co- mentors and advisors who will provide their multidisciplinary expertise in training Dr. Kim in the theoretical and technical aspects of hematopoiesis and inflammation. Through UCLA's Clinical and Translational Science Institute (CTSI), Dr. Kim will have access to numerous career development seminars that address such topics as grant writing, manuscript preparation, and ethical research. She will also take graduate courses to obtain further training in immunology, pharmacology, hematopoiesis, and biostatistics. Dr. Kim is fortunate to have the full support of her institution, as well as the man advantages of carrying out her research project at UCLA, a renowned research center. This proposal outlines a 5-year research and career development plan that will prepare Dr. Kim to become an independent physician-scientist engaged in high-level scientific research. This project aims to elucidate the mechanisms of acute and severe AI, and to test novel therapies and their mechanisms of action in a mouse model. Dr. Kim recently characterized a mouse model of AI induced by heat-killed Brucella abortus (BA) that mimics the characteristics of human ICU anemia, including rapid onset, hypoferremia despite preserved iron stores, shortened erythrocyte lifespan, and depressed erythropoiesis. Using the BA mouse model of AI, Specific Aim 1a seeks to comprehensively investigate the underlying mechanisms, including potential contributions of reduced erythropoietin (EPO) production, decreased EPO receptor activity, and altered erythropoietic differentiation. One specific inflammatory cytokine that has been implicated in the development of AI is interferon-γ (IFN-γ). Using IFN-γR1-/- mice, Specific Aim 1b seeks to examine the mechanisms of IFN-γ involvement in erythroid progenitor differentiation, macrophage activation, and erythrocyte lifespan. Two promising candidates for the treatment of AI are an orally bioavailable prolyl-hydroxylase (PHD) inhibitor that has been shown to improve anemia in patients with chronic renal failure, and erythroferrone (ERFE), a hormone newly identified by Dr. Kim's group that is induced by EPO and suppresses hepcidin expression. For Specific Aim 2a, Dr. Kim will test the PHD inhibitor in the BA mouse model in order to investigate its mechanistic and potential therapeutic effects in acute and severe inflammatory anemia. For Specific Aim 2b, Dr. Kim will use murine recombinant ERFE in the BA mouse model in order to investigate the effects on erythropoiesis and recovery in acute and severe AI. This project seeks to answer important mechanistic questions about AI, and investigate the use of novel therapies. With this work, Dr. Kim aims to advance our knowledge and potential treatments of the common but poorly understood condition of ICU anemia.