CHRONIC KIDNEY DISEASE ADVERSELY INFLUENCES VASCULAR FUNCTIONS

描述(申请人提供)：我们的长期目标是确定慢性肾脏疾病(CKD)如何影响CKD患者动静脉瘘(AVF)衰竭的细胞和分子机制。对于许多CKD患者来说，血液透析是首选的治疗方法；美国约有47万名患者正在接受血液透析治疗。血液透析治疗的成功需要功能正常的动静脉通路(AVF)。然而，在动静脉瘘建立后的两年内，近50%的瘘管失败，通常是由于血管平滑肌细胞(SMCs)的新生内膜增生。预防或纠正AVF故障的成本每年超过10亿美元！因此，了解新生内膜形成的机制可能会导致有针对性的治疗策略。我们在CKD小鼠中创建了一个模拟患者事件的AVF模型。在患有CKD的小鼠中，我们发现了动静脉瘘新生内膜形成的线索。首先，我们的动静脉瘘模型小鼠骨髓细胞、FSP-1阳性细胞和炎症细胞的FSP-1表达增加。第二，有证据表明CKD患者失败的动静脉动静脉瘘存在内皮-间充质转化(EnMT)。第三，CKD激活Notch信号，特别是RBP-J：转录因子。因此，我们假设CKD诱导Notch/RBP-J激活，从而促进EnMT，导致内皮屏障功能障碍，炎性细胞和BM细胞渗透，导致新生内膜形成。为了验证我们的假设，我们将在CKD中创建AVF，并将其与转基因方法相结合。这将使我们：1)确定CKD诱导的EnMT是否加速动静脉曲张的内皮屏障功能障碍和新生内膜的形成。2)探讨表达FSP-1的骨髓来源细胞在CKD过程中如何促进动静脉瘘新生内膜的形成。3)探讨RBP-J在慢性肾脏病新生内膜形成中的作用。因此，我们的结果将直接解决CKD的存在加速新生内膜形成和AVF衰竭的机制。总之，我们建议的实验结果可能为理解与新生内膜形成相关的透析途径失败这一临床相关且代价高昂的问题背后的机制提供了一个新的范式。

DESCRIPTION (provided by applicant): Our long-term goal is to identify how chronic kidney disease (CKD) influences the cellular and molecular mechanisms underlying arteriovenous fistula (AVF) failure in patients with CKD. For many patients with CKD, hemodialysis is the preferred method of treatment; there are ~470,000 patients receiving hemodialysis treatments in U.S. The success of hemodialysis treatments requires a functioning arteriovenous access (AVF). However, in the 2 years following creation of the AVF, nearly 50% of the fistulas fail, generally due to neointima hyperplasia of vascular smooth muscle cells (SMCs). The costs of preventing or correcting AVF failure exceed $1 billion per year! Therefore, understanding the mechanisms underlying the development of the neointima could lead to a directed therapeutic strategy. We created a model of AVF in CKD mice that mimics events occurring in patients. In mice with CKD, we have uncovered clues to neointima formation in AVF. First, there is increased expression of FSP-1 in BM cells and FSP-1-positive cells and inflammatory cells in our mouse model of AVFs. Second, there is evidence of endothelial-mesenchymal transition (EnMT) in failed AVFs from CKD patients. Third, CKD activates Notch signaling and specifically, the RBP- J: transcription factor. Thus, we hypothesize that CKD-induced activation of Notch/RBP-J that promotes EnMT resulting in endothelial barrier dysfunction with infiltration of inflammatory and BM cells, leading to neointima formation. To test our hypothesis, we will create AVF in CKD and combined it with transgenic approaches. This will allow us: 1) to determine if CKD-induced EnMT accelerates endothelial barrier dysfunction and neointima formation in AVFs. 2) To identify how BM-derived cells expressing FSP-1 increase neointima formation in AVFs during CKD. 3) To investigate if RBP-J: contributes to neointima formation in CKD. Thus, our results will directly address the mechanism by which the presence of CKD accelerates neointima formation and AVF failure. In summary, results from our proposed experiments could provide a new paradigm for understanding mechanisms underlying the clinically relevant, costly problem of the failing dialysis access related to neointima formation.