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Promoting hematopoietic regeneration after chemo by rescheduling homeostasis

通过重新安排体内平衡促进化疗后造血再生

基本信息

批准号：
8903518
负责人：
Joseph Michael Scandura
金额：
$ 54.66万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903518
关键词：
Area Back Benchmarking Bone Marrow Bone Marrow Cells CDKN1C gene CSF3 gene Cell Cycle Cell Proliferation Cell physiology Cells Clinical Complication Data Development Dose Endothelial Cells Environmental Wind Fetal Liver Flow Cytometry Fostering GTP-Binding Protein Regulators Gene Targeting Goals Hand Health Hematological Disease Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemorrhage Homeostasis Immunofluorescence Immunologic Immunohistochemistry Infection Knock-out Lead Learning Life Malignant Neoplasms Mediating Mediator of activation protein Megakaryocytes Methodology Mission Mononuclear Mus Myelosuppression National Heart, Lung, and Blood Institute Natural regeneration Outcome Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Prevention Process Public Health Publishing RGS1 gene Recovery Recruitment Activity Regulation Research Research Personnel Research Support SLAM protein Safety Signal Pathway Signal Transduction Specific qualifier value Stem cells Stress Testing Therapeutic Tissues Transforming Growth Factors Translations Transplantation United States National Institutes of Health Work adult stem cell base biological adaptation to stress cancer therapy cell killing cell type chemokine chemotherapy clinical practice cytokine exhaustion improved inhibitor/antagonist innovation interest medical schools meetings neoplastic neoplastic cell novel strategies pre-clinical preclinical study receptor response restoration self-renewal stem

项目摘要

DESCRIPTION (provided by applicant): Myelosuppression is the most common life-threatening complication of anti-neoplastic therapy. A great deal is known about the activation of hematopoietic stem and progenitor cells (HSPCs) to initiate recovery from myelosuppression. Yet it is not known how these processes wind down to allow hematopoiesis to return to homeostasis. The long-term goal of this research is to develop new approaches for treating multi-lineage myelosuppression. The objective of this application is to identify the signaling pathways that check recovery and reinstate homeostasis during hematopoietic regeneration after myelotoxic chemotherapy. The central hypothesis is that TGF β signaling is activated during recovery from myelotoxic stress, and this induces a transcriptional response in HSPCs that re-establishes their quiescence and dampens hematopoietic regeneration. The rationale for the proposed studies is that, once we understand how homeostasis is restored after hematopoietic stress, we can pharmacologically manipulate the recovery to limit chemotherapy-induced myelosuppression and allow more efficacious treatments to be delivered safely. Three specific aims will be pursued to test the hypothesis. Aim 1: Identify how TGF β signaling is activated during recovery from myelotoxic stress. Aim 2: Define how TGF β target genes in HSPCs re-establish homeostasis during stress recovery. Aim 3: Determine how TGF β blockade can be safely combined with chemotherapy to minimize myelosuppression. All three aims are well supported by preliminary studies and use methodologies that have already been established to be feasible in the applicants' hands. The first aim will identify the bone marrow cells from which TGF β originates and determine how latent TGF β is locally activated during recovery from myelotoxic therapy. The second aim will identify the downstream signaling pathways that mediate TGF β-enforced restoration of HSPC homeostasis following chemotherapy. With the third aim, well-controlled pre-clinical studies will assess the long-term safety and potential efficacy of combining TGF β pathway inhibitors with chemotherapy as a strategy to minimize myelosuppression. Currently, TGF β pathway inhibitors are being clinically developed for their direct anti-neoplastic activities. Ultimately, the proposed studies are expected to show that TGF β blockade after chemotherapy can limit myelosuppression while it is augmenting tumor cell kill: a new double-edged sword to attack cancer. This contribution is significant because it opens the door to new classes of agents that promote multi-lineage hematopoietic regeneration by modulating the return of HSPCs to steady-state quiescence. The proposed research is innovative because it is a substantial departure from the status quo and challenges the de facto paradigm that homeostasis is passively reestablished as cytokine levels normalize after stress. This work is expected to vertically advance our understanding of the hematopoietic adaptations to stress and it is likely that what is learned here can be extrapolated to other adult stem cell types that are induced in response to tissue damage.

描述（由申请方提供）：骨髓抑制是抗肿瘤治疗最常见的危及生命的并发症。关于造血干细胞和祖细胞（HSPC）的激活以启动从骨髓抑制中恢复的大量已知。然而，目前尚不清楚这些过程如何结束以使造血恢复稳态。这项研究的长期目标是开发治疗多系骨髓抑制的新方法。本申请的目的是鉴定在骨髓毒性化疗后造血再生期间检查恢复和恢复稳态的信号通路。中心假设是TGF β信号传导在从骨髓毒性应激恢复期间被激活，并且这诱导HSPC中的转录应答，其重新建立其静止并抑制造血再生。提出研究的基本原理是，一旦我们了解造血应激后体内平衡是如何恢复的，我们就可以控制恢复，以限制化疗诱导的骨髓抑制，并允许安全地提供更有效的治疗。为了检验这一假设，将追求三个具体目标。目的1：确定TGF β信号在骨髓毒性应激恢复过程中是如何激活的。目的2：明确HSPCs中TGF β靶基因在应激恢复过程中如何重建稳态。目的3：确定TGF β阻断剂如何安全地与化疗联合使用，以最大限度地减少骨髓抑制。所有这三个目标都得到了初步研究的充分支持，并使用了申请人手中已经确立的可行方法。第一个目标是鉴定TGF β来源的骨髓细胞，并确定在骨髓毒性治疗恢复期间潜伏的TGF β如何局部激活。第二个目标将确定介导化疗后TGF β增强的HSPC稳态恢复的下游信号传导途径。关于第三个目标，对照良好的临床前研究将评估TGF β通路抑制剂与化疗联合作为最小化骨髓抑制策略的长期安全性和潜在疗效。目前，TGF β通路抑制剂因其直接抗肿瘤活性而正在临床上开发。最终，拟议的研究预计将表明，化疗后的TGF β阻断可以限制骨髓抑制，同时增加肿瘤细胞杀伤：一把新的双刃剑来攻击癌症。这一贡献是重要的，因为它打开了大门，以促进多谱系造血再生，通过调节HSPC的恢复到稳态静止的新类别的代理。拟议的研究是创新的，因为它是一个实质性的偏离现状，并挑战事实上的范式，即被动重建细胞因子水平正常化后的压力。这项工作预计将垂直推进我们对造血适应压力的理解，并且很可能这里学到的东西可以外推到组织损伤诱导的其他成体干细胞类型。