课题基金 / 基金详情

Defining LncRNA Function in normal and Shwachman Diamond Syndrome Myelopoiesis

Defining LncRNA Function in normal and Shwachman Diamond Syndrome Myelopoiesis
定义正常和 Shwachman Diamond 综合征骨髓生成中的 LncRNA 功能
批准号:
10320386
负责人:
CARL D NOVINA
金额:
$44.13万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-01-15 至 2023-12-31

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中文摘要
翻译
项目摘要 Shwachman-Diamond综合征(SDS)是一种遗传性骨髓衰竭综合征, 系统.然而,SDS中的血液学缺陷仍然缺乏表征。我们用单细胞RNA 测序以鉴定造血干细胞(HSC)中特异性增加的TGF β 1信号传导, 多能祖细胞(MPPs),但不是谱系定型祖细胞。我们还发现, 正常情况下下调TGF β 1信号传导的lncRNA的表达。我们的数据表明SDS骨中的lncRNA 骨髓衰竭 为了明确lncRNA在正常骨髓生成中的功能以及它们的失调在SDS中的致病性,我们 将使用最近开发的酵母三杂交(Y3 H)测定系统地定义lncRNA蛋白 在正常和疾病造血中鉴定的100种lncRNA的相互作用。Y3 H能够检测低- 丰度和低亲和力相互作用lncRNA-蛋白质相互作用。覆盖lncRNA-蛋白质相互作用 现有的PPI网络将定义正常骨髓细胞生成的lncRNA调节途径, SDS中的失调。因为我们将筛选100个独立lncRNA的重叠lncRNA片段, 这些研究将使系统的lncRNA结构-功能分析成为可能。通过此获得的信息 结构-功能分析对于建立序列和/或结构参数是关键, 能够预测lncRNA-蛋白质结合活性,从而推进我们对生物学的理解。 lncRNA,即使是那些不包括在这个初始筛选。 然后,我们将验证lncRNA在造血和改变TGF β活化中的作用。具体来说,我们将使用 CD 34+细胞耗尽SBDS并增加(通过异位表达)或减少(通过敲低)lncRNA 和它们的相互作用蛋白质,并测试这些作用在自我更新,髓系定型,增殖, 细胞死亡、氧化应激、炎症和TGF β活化。为了进一步测试特异性lncRNA在 TGF β 1信号传导,我们也将测试TGF β 1抑制剂拯救正常造血功能的能力。我们将 鉴定受影响亚群中的TGF β-应答基因,其可以作为新SDS疗法的靶点,以及 检测其在SDS造血中的作用。因此,这些研究将(1)鉴定lncRNA、蛋白质和lncRNA- 指导正常和SDS致病性骨髓功能的蛋白质相互作用;(2)开发一个平台, 系统地研究lncRNA;和(3)提供临床前证据,可以支持临床试验靶向 未来SDS治疗的lncRNA导向途径。
英文摘要
Project Summary Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome affecting multiple organ systems. However, the hematological defects in SDS remain poorly characterized. We used single cell RNA sequencing to identify increased TGF signaling specifically in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), but not lineage-committed progenitors. We also identified significantly reduced expression of lncRNAs that normally down-regulate TGF signaling. Our data implicate lncRNAs in SDS bone marrow failure. To define how lncRNAs function in normal myelopoiesis and how their dysregulation is pathogenic in SDS, we will use a recently developed yeast three hybrid (Y3H) assay to systematically define lncRNA-protein interactions for 100 lncRNAs identified in normal and disease hematopoiesis. Y3H is capable of detecting low- abundance and low-affinity interactions lncRNA-protein interactions. Overlaying the lncRNA-protein interacting onto existing PPI networks will define lncRNA-regulated pathways of normal myelopoiesis and their dysregulation in SDS. Because we will screen of overlapping lncRNA fragments of 100 individual lncRNAs, these studies will enable systematic lncRNA structure-function analyses. The information obtained through this structure-function analysis will be critical for establishing sequence and/or structural parameters which may enable prediction of lncRNA-protein binding activity, thereby advancing our understanding of the biology of lncRNAs, even those not included in this initial screen. We will then validate roles for lncRNAs in hematopoiesis and altered TGF activation. Specifically, we will use CD34+ cells depleted of SBDS and increase (by ectopic expression) or decrease (by knockdown) lncRNAs and their interacting proteins and test these effects in self renewal, myeloid lineage commitment, proliferation, cell death, oxidative stress, inflammation and TGF activation. To further test roles for specific lncRNAs in TGF signaling, we will also test the ability of TGF inhibitors to rescue normal hematopoietic function. We will identify TGF-responsive genes in affected subpopulations that could be targeted for novel SDS therapies, and test their function in SDS hematopoiesis. Thus, these studies will (1) identify lncRNAs, proteins, and lncRNA- protein interactions directing normal and SDS pathogenic myeloid function; (2) develop a platform for systemically studying lncRNAs; and (3) provide pre-clinical evidence that could support a clinical trial targeting lncRNA-directed pathways for future SDS therapy.
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