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

BLR

• 批准号: 10451496
• 负责人: AMBRA POZZI
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451496
• 关键词: Affect; American; Animal Model; Area; Award; Binding; Biology; CCL2 gene; Cell Nucleus; Cells; Cessation of life; Chromatin; Chronic Kidney Failure; Clinical Management; Collagen; Collagen Receptors; Collagen Type IV; DDR1 gene; DNA; Deposition; Development; Disease; Doctor of Philosophy; Down-Regulation; ECM receptor; End stage renal failure; Epidermal Growth Factor Receptor; Etiology; Extracellular Matrix; Fibrosis; Funding; Funding Agency; Generations; Genetic; Genetic Transcription; Goals; Health; Healthcare; Homeostasis; Human; In Vitro; Inflammatory; Injury; Injury to Kidney; Integrins; International; Journals; Kidney; Kidney Diseases; Ligands; Mediating; Mission; Morbidity - disease rate; NADPH Oxidase; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Nuclear; Nuclear Translocation; Outcome; Oxidative Stress; Pathology; Pathway interactions; Peer Review; Peptides; Pharmaceutical Preparations; Phosphorylation; Play; Pre-Clinical Model; Privatization; Production; Profibrotic signal; Protein Tyrosine Phosphatase; Publications; Publishing; Quality of life; RNA-Binding Proteins; Reactive Oxygen Species; Receptor Activation; Regulation; Renal function; Research; Ribonucleoproteins; Role; Scientist; Sclerosis; Signal Transduction; Site; Societies; Therapeutic; Time; Transforming Growth Factor beta Receptors; Tyrosine Phosphorylation; United States National Institutes of Health; Universities; Veterans; Work; active duty; antifibrotic treatment; base; career; clinical investigation; discoidin receptor; editorial; fused in sarcoma; improved; in vivo; indexing; inhibitor; kidney fibrosis; medical schools; military veteran; mortality; mouse development; novel; novel strategies; prevent; professor; programs; promoter; receptor; recruit; small molecule; small molecule inhibitor; transcription factor

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.

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 健康和疾病的内稳态。由于ECM的进行性积累导致纤维化，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 有效的抗纤维化疗法。在基质受体中，PI侧重于整联蛋白（VA Merit Review）和 盘状结构域受体（DDRs）（NIH/NIDDK R 01）在调节胶原合成和降解中的作用 肾损伤 PI的研究小组有证据表明，胶原受体整合素α1β1是纤维化的负调节因子， 通过以下方式发挥保护作用：1）以配体非依赖性方式下调TGF-β受体的活化 和抑制Smad依赖性促纤维化信号传导; 2）抑制EGF受体的活化; 3） 负调节NADPH氧化酶的组装，从而减少氧化应激;和4）防止 磷酸化和核转位的核糖核蛋白融合在肉瘤（FUS）（VA Merit评论）。 与整合素α1β1相反，整合素α2β1和DDR 1是纤维化的阳性调节因子，来自PI的研究 研究表明，整合素α2β1或DDR 1的遗传缺失保护小鼠免于肾脏发育 损伤后纤维化PI的小组提供了强有力的证据，表明这两种基质的有害作用 受体存在于它们激活下游促炎（MCP-1）和促纤维化（Stat-3）的能力 信号此外，PI提供了新的发现，即DDR 1可以通过以下方式调节胶原蛋白的产生： 转移到细胞核，在那里它定位于染色质以促进胶原蛋白的转录。 基于这些发现，PI的目标是设计基于肽的抑制剂和小分子抑制剂， 这些受体和/或它们的下游信号传导。PI的研究小组有强有力的证据表明，小分子和 分别抑制整合素α2β1和FUS核转位的基于肽的方法具有很大的优势。 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停止肾纤维化的策略，并确定新的， 潜在的可靶向分子，由整联蛋白和DDR选择性调节。 PI研究发表在高评价期刊上，包括Journal of American Society of Nephrology，Kidney 国际，矩阵生物学，临床研究杂志，仅举几例。为了取得成功，PI 已经组建了一个由细胞生物学家，药物化学家，细胞穿透肽生产专家组成的团队， 介导的治疗分子，以及大学和VA站点的肾病学家。PI的研究领域 与我们的退伍军人高度相关，因为肾纤维化和随之而来的终末期肾病是 在现役军人和退伍军人中。PI及其团队执行的工作将导致 开发新的策略来阻止和理想地预防肾纤维化，从而提高 我们退伍军人的生活