CHRONIC KIDNEY DISEASE ADVERSELY INFLUENCES VASCULAR FUNCTIONS

描述（由申请人提供）：我们的长期目标是确定慢性肾病（CKD）如何影响慢性肾病患者动静脉瘘（AVF）失败的细胞和分子机制。对于许多CKD患者，血液透析是首选的治疗方法;在美国约有470，000例患者接受血液透析治疗。血液透析治疗的成功需要功能正常的动静脉通路（AVF）。然而，在创建AVF后的2年内，近50%的瘘失败，通常是由于血管平滑肌细胞（SMC）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，了解新生内膜发生的机制可能会导致定向治疗策略。 我们在CKD小鼠中创建了一个AVF模型，模拟患者中发生的事件。在患有CKD的小鼠中，我们发现了AVF中新生内膜形成的线索。首先，在我们的AVF小鼠模型中，BM细胞和FSP-1阳性细胞和炎性细胞中FSP-1的表达增加。其次，有证据表明CKD患者AVF失败时存在内皮-间质转化（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诱导的促进EnMT的Notch/RBP-J活化导致内皮屏障功能障碍，伴有炎症和BM细胞浸润，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。这将使我们能够：1）确定CKD诱导的EnMT是否加速AVF中的内皮屏障功能障碍和新生内膜形成。2)确定表达FSP-1的BM衍生细胞如何增加CKD期间AVF中的新生内膜形成。3)研究RBP-J是否有助于CKD中的新生内膜形成。因此，我们的研究结果将直接阐明CKD加速新生内膜形成和AVF衰竭的机制。总之，我们提出的实验结果可以为理解与新生内膜形成相关的透析通路失败的临床相关、昂贵问题的潜在机制提供新的范例。

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.