Emergency Myelopoiesis Pathways in the Control of Blood Production

控制血液产生的紧急骨髓生成途径

• 批准号: 10379332
• 负责人: Emmanuelle Passegue
• 金额: $ 81.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379332
• 关键词: Address; Aging; Biological Process; Blood; Blood Cells; Bone Marrow; Cell Lineage; Cells; Correlative Study; Development; Differentiation Therapy; Disease; Emergency Situation; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Cell Production; Hematopoietic stem cells; Heterogeneity; Human; Inflammation; Inflammatory; Link; Lymphoid; MPP2 gene; MPP3 gene; Malignant - descriptor; Maps; Molecular; Multipotent Stem Cells; Mus; Myelogenous; Myelopoiesis; Myeloproliferative disease; National Heart, Lung, and Blood Institute; Natural regeneration; Output; Pathway interactions; Patients; Physiological; Population; Process; Production; Regulation; Regulatory Pathway; Research Project Grants; Sampling; Signal Transduction; Stress; Therapeutic Intervention; biophysical properties; cytokine; granulocyte; hematopoietic stem cell differentiation; interest; leukemia; macrophage; new therapeutic target; novel; progenitor; self-renewal; stem; stem cell function; therapeutically effective; translational applications

PROJECT DESCRIPTION Activation of myeloid differentiation pathways always accompanies blood regeneration after stress, the development of hematological malignancies and physiological aging. However, our understanding of what activate myelopoiesis in such deregulated conditions is still very limited. Our goals in this NHLBI OIA application are to (1) decipher the cellular and molecular mechanisms controlling emergency myelopoiesis pathways; (2) understand how the hijacking of these mechanisms contributes to deregulated hematopoietic stem cell (HSC) function and blood production in stress, disease and aging; and (3) identify novel targets for therapeutic interventions aimed at correcting blood production in these deregulated contexts. We recently showed that the output of the myeloid lineage at steady state reflects the differential production by HSCs of a small number of myeloid-biased multipotent progenitors (MPP), called MPP2 and MPP3, and a large number of lymphoid-biased MPPs, known as MPP4 or LMPPs, which both give rise to granulocyte/macrophage progenitors (GMP) and contribute to myelopoiesis (Pietras et al., 2015). During blood regeneration, we found that HSCs are transiently induced to overproduce MPP2/3 and that MPP4 are reprogrammed towards almost exclusive myeloid output, in large part due to cytokine stimulation and the triggering of specific regulatory pathways (Reynaud et al., 2011; Pietras et al., 2015; 2016). An important consequence of the activation of this myeloid regeneration axis is the formation of defined GMP clusters in the bone marrow (BM) cavity, which drive the local overproduction of granulocytes (Hérault et al., submitted). This newly identified process of GMP cluster formation is finely tuned by the timed release of important BM niche signals, and transient activation of an inducible self-renewal network in a subset of GMPs. Altogether, the remodeling of the MPP compartment and induction of GMP cluster formation represent novel and targetable mechanisms of emergency myelopoiesis, which are transiently activated during blood regeneration but are continuously triggered in myeloid malignancies. We are now interested in exploring the contribution of these mechanisms to other deregulated contexts such as inflammation and aging, and in answering an exciting set of new questions that have directly emerged from these studies. In particular, we would like to understand the molecular and cellular basis for the functional heterogeneity observed in the MPP and GMP compartments, map the mechanisms of HSC lineage commitment and their links to the pro-inflammatory BM milieu, and decipher the contribution of the biophysical properties of the BM niche to HSC and myeloid progenitor fate decisions. We also would like to conduct correlative studies with human cells and leukemic patient samples to establish whether aberrant activation of similar emergency myelopoiesis pathways contribute to deregulated blood production in humans. Taken together, these studies are paradigm shifting for understanding the mechanisms controlling blood regeneration and their deregulations in leukemia and aging, and for identifying new targets for translational applications and the treatment of a broad range of blood disorders in humans. While many current therapies treat blood disorders by targeting the malignant and/or overproduced blood cells, our objective is to identify new biological process upstream of these cells to treat blood disorders by using anti-HSC differentiation therapies and by restoring proper regulation of blood production.

项目描述 粒细胞分化途径的激活总是可容纳压力后的血液再生， 血液学恶性肿瘤和身体衰老的发展。但是，我们对在这种不受管制的条件下激活骨髓虫的理解仍然非常有限。我们在此NHLBI OIA申请中的目标 是（1）破译控制紧急骨髓疫苗途径的细胞和分子机制； （2） 了解这些机制的劫持如何有助于失控的造血干细胞（HSC） 压力，疾病和衰老中的功能和血液产生； （3）确定旨在在这些放松管制的情况下纠正血液产生的热干预措施的新目标。我们最近表明，稳态下的髓样谱系的输出反映了少数髓样偏置的多能祖细胞（MPP）的HSC的差异产生，称为MPP2和MPP3，以及大量淋巴样偏见 MPP，称为MPP4或LMPP，它们都会产生粒细胞/巨噬细胞祖细胞（GMP）和 造成脊髓虫的贡献（Pietras等，2015）。在血液再生期间，我们发现HSC是瞬时的 诱导过度生产MPP2/3，并且该MPP4被重新编程为几乎独家的髓样输出， 在很大程度上是由于细胞因子刺激和特定调节途径的触发（Reynaud等， 2011; Pietras等人，2015年； 2016）。该髓样再生轴激活的重要结果 是骨髓（BM）腔中定义的GMP簇的形成，它驱动局部过量生产 粒细胞（Hérault等人，提交）。 GMP群集形成的新鉴定的过程很细微 通过重要的BM利基信号的定时发布和诱导的自我更新的瞬时激活来调整 网络在GMP的子集中。总之，MPP室的重塑和GMP簇的诱导形成代表了紧急骨髓膜的新颖和可靶向机制，这些机制是短暂的 在血液再生过程中被激活，但在髓样恶性菌中不断触发。现在，我们有兴趣探索这些机制对其他放松管状的情况（例如炎症）的贡献 和衰老，并回答了一系列令人兴奋的新问题，这些问题直接从这些研究中引起。在 特别是，我们想了解在MPP和GMP室中观察到的功能异质性的分子和细胞基础，绘制HSC谱系投入的机制及其链接 对促炎的BM环境，并破译BM生物物理生物物理特性的贡献 对HSC和髓样祖细胞脂肪的决定。我们也想与人类进行相关研究 细胞和白血病患者样本，以确定异常激活类似的紧急骨髓病变的异常 途径有助于人类的血液产生。综上所述，这些研究是范式 转移以了解控制血液再生的机制及其在白血病中的消失 和老化，并确定用于翻译应用的新目标以及广泛的处理 人类的血液疾病。而许多当前疗法通过靶向恶性治疗血液疾病 和/或过量生产的血细胞，我们的目标是确定这些细胞上游的新生物过程 通过使用抗HSC分化疗法并通过恢复适当的血液来治疗血液疾病 生产。