BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)

PI是细胞外基质(ECM)受体生物学以及这些受体如何控制ECM的专家 健康和疾病的动态平衡。随着ECM的逐渐积累导致纤维化，PI的目标是 确定ECM受体控制基质合成/降解的机制，以设计更多 有效的抗纤维化治疗。在基质受体中，PI侧重于整合素(VA Merit Review)和 盘状结构域受体(NIH/NIDDK R01)在心脏胶原合成和降解中的作用 肾损伤。 Pi‘s小组有证据表明，胶原受体整合素α1β1是纤维化的负调控因子，它 通过以下方式发挥保护作用：1)以不依赖配体的方式下调转化生长因子-β受体的激活 抑制Smad依赖的促纤维化信号；2)抑制EGF受体的激活；3) 负调控NADPH氧化酶的组装，从而减少氧化应激；以及4)防止 肉瘤(FUS)中融合核糖核蛋白的磷酸化和核转位(VA优点评论)。 与整合素α1β1相反，整合素α2β1和Ddr1是纤维化的阳性调节因子，来自PI的研究 研究小组指出，整合素α2或β1的基因缺失可以保护小鼠免受肾脏发育的影响 损伤后的纤维化。Pi‘s群提供了强有力的证据，证明这两种基质的有害作用 受体存在于它们激活下游促炎症(MCP-1)和促纤维化(Stat-3)的能力 发信号。此外，PI提供了新的发现，DDR1可以通过以下方式调节胶原的产生 移位到细胞核，在那里它定位于染色质，促进胶原的转录。 基于这些发现，PI的目标是设计基于多肽的抑制剂和小分子抑制剂来靶向 这些受体和/或它们的下游信号。派的小组有强有力的证据表明，小分子和 基于多肽的方法分别抑制整合素α2β1和FUS核转位，具有很大的 有望在体外和动物模型中用作抗纤维化方法。基于这些令人兴奋的结果 PI目前正在完善预防和理想地阻止肾脏纤维化的策略，并确定新的和 受整合素和DDRs选择性调控的潜在靶向分子。 PI研究发表在包括《美国肾脏学会杂志》在内的高评级期刊上 《国际》、《基质生物学》、《临床调查杂志》，仅举几例。为了取得成功，PI 已经组建了一支由细胞生物学家、药物化学家和细胞穿透肽产生专家组成的团队- 介导的治疗分子，以及大学和退伍军人事务部的肾病学家。国际和平研究所的研究领域 与我们的退伍军人高度相关，因为肾脏纤维化和随之而来的终末期肾脏疾病 现役军人和退伍军人中的普通成员。PI和她的团队所做的工作将导致 开发新的策略来阻止和理想地预防肾脏纤维化，从而提高肾纤维化的质量 我们退伍军人的生命。

The PI is an expert in extracellular matrix (ECM) receptor biology and how these receptors control ECM homeostasis in health and disease. As progressive accumulation of ECM leads to fibrosis, the PI goal is to determine the mechanisms whereby ECM receptors control matrix synthesis/degradation in order to devise more effective anti-fibrotic therapies. Among the matrix receptors the PI focuses on integrins (VA Merit Review) and discoidin domain receptors (DDRs) (NIH/NIDDK R01) in the regulation of collagen synthesis and degradation in kidney injury. The PI’s group has evidence that the collagen receptor integrin α1β1 is a negative regulator of fibrosis and it plays a protective role by: 1) downregulating the activation of the TGF-β receptor in a ligand independent manner and dampening Smad-dependent pro-fibrotic signaling; 2) inhibiting the activation of the EGF receptor; 3) negatively regulating the assembly of the NADPH oxidase thus reducing oxidative stress; and 4) preventing the phosphorylation and nuclear translocation of the ribonucleoprotein Fused in Sarcoma (FUS) (VA Merit Review). In contrast to integrin α1β1, integrin α2β1 and DDR1 are postive regulators of fibrosis and studies from the PI group indicate that genetic deletion of integrin α2β1 or DDR1 protects mice from the development of kidney fibrosis after injury. The PI’s group provides strong evidence that the deleterious action of these two matrix receptors resides in their ability to activate pro-inflammatory (MCP-1) and pro-fibrotic (Stat-3) downstream signaling. In addition, the PI provides the novel finding that DDR1 can regulate collagen production by translocating to the nucleus where it localizes to chromatin to promote the transcription of collagen. Based on these findings, the PI’s goal is to devise peptide-based inhibitors and small molecule inhibitors to target these receptors and/or their downstream signaling. The PI’s group has strong evidence that small-molecule and peptide-based approaches to inhibit integrin α2β1 and FUS nuclear translocation, respectively, have a great promise to be used as anti-fibrotic approaches in vitro and in animal models. Based on these exciting results the PI is currently refining strategies to prevent and ideally halt kidney fibrosis and identifying novel and potentially targetable molecules selectively regulated by integrins and DDRs. The PI studies are published in high rated journals including Journal of American Society of Nephrology, Kidney International, Matrix Biology, Journal of Clinical Investigation, to name a few. In order to be successful, the PI has assembled a team of cell biologists, medicinal chemists, experts in the generation of cell-penetrating peptide- mediated therapeutic molecule, and nephrologists both at the University and VA site. The PI’s area of research is highly relevant to our Veterans because kidney fibrosis and consequent end stage kidney disease are commons in active duty military and Veterans. The work performed by the PI and her team will lead to the development of novel strategies to halt and ideally prevent kidney fibrosis and, hence, improve the quality of lives of our Veterans.