Promoting hematopoietic regeneration after chemo by rescheduling homeostasis

描述(申请人提供)：骨髓抑制是抗肿瘤治疗中最常见的危及生命的并发症。关于造血干细胞和祖细胞(HSPC)的激活以启动骨髓抑制的恢复，人们已经知道了很多。然而，目前尚不清楚这些过程是如何结束的，从而使造血恢复到动态平衡。这项研究的长期目标是开发治疗多谱系骨髓抑制的新方法。这项应用的目的是确定在骨髓毒性化疗后的造血再生过程中检查恢复和恢复体内平衡的信号通路。核心假设是转化生长因子β信号在骨髓毒性应激恢复过程中被激活，这诱导了HSPC的转录反应，重新建立了它们的静止状态，并抑制了造血再生。这项拟议研究的基本原理是，一旦我们了解了造血应激后体内平衡是如何恢复的，我们就可以通过药物操作来限制化疗引起的骨髓抑制，并允许更有效的治疗安全地进行。将追求三个具体目标来检验这一假设。目的1：明确骨髓毒性应激恢复过程中转化生长因子β信号的激活情况。目的2：明确转化生长因子β靶基因在应激恢复过程中如何重建内环境平衡。目的3：确定如何安全地将转化生长因子β阻断与化疗相结合以减少骨髓抑制。所有这三个目标都得到了初步研究的很好支持，并使用了已经在申请者手中确立为可行的方法。第一个目标是确定转化生长因子β起源的骨髓细胞，并确定潜在的转化生长因子β在骨髓毒性治疗恢复过程中如何局部激活。第二个目标将确定介导转化生长因子β促进化疗后HSPC动态平衡恢复的下游信号通路。对于第三个目标，良好控制的临床前研究将评估转化生长因子β途径抑制剂与化疗相结合作为减少骨髓抑制的策略的长期安全性和潜在疗效。目前，转化生长因子β途径抑制剂因其直接的抗肿瘤活性而被临床开发。最终，拟议的研究有望表明，化疗后阻断转化生长因子β可以限制骨髓抑制，同时增强对肿瘤细胞的杀伤力：一把新的治疗癌症的双刃剑。这一贡献意义重大，因为它为通过调节HSPC回到稳定静止状态而促进多血统造血再生的新型药物打开了大门。这项拟议的研究具有创新性，因为它与现状有很大的不同，并挑战了事实上的范式，即随着细胞因子水平在应激后恢复正常，动态平衡是被动重建的。这项工作有望垂直推进我们对应激的造血适应的理解，并很可能将在这里学到的知识外推到其他类型的成人干细胞，这些类型是针对组织损伤而诱导的。

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.