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）受体生物学的专家，以及这些受体如何控制ECM 健康和疾病中的稳态。随着ECM的渐进积累导致纤维化，PI目标是 确定ECM接收器控制矩阵综合/降解的机制，以设计更多 有效的抗纤维化疗法。在矩阵受体中，PI专注于整联蛋白（VA值得审查）和 在调节胶原蛋白合成和降解中，盘状蛋白结构域受体（DDR）（DDR）（NIH/NIDDK R01） 肾脏受伤。 PI组有证据表明胶原受体整合蛋白α1β1是纤维化的负调节剂，IT 通过以下方式发挥保护作用：1）以独立的方式下调TGF-β受体的激活 并抑制SMAD依赖性促纤维化信号传导； 2）抑制EGF受体的激活； 3） 负调节NADPH氧化酶的组装，从而减少氧化应激； 4）防止 肉瘤（FUS）中核糖蛋白融合的磷酸化和核易位（VA值得评论）。 与整联蛋白α1β1相反，整联蛋白α2β1和DDR1是纤维化的后期调节剂，并且来自PI的研究 组表明整联蛋白α2β1或DDR1的遗传缺失可保护小鼠免受肾脏的发展 受伤后的纤维化。 PI小组提供了有力的证据，表明这两个矩阵的有害行动 受体具有激活促炎（MCP-1）和促纤维化（Stat-3）下游的能力 信号。此外，PI提供了新的发现，即DDR1可以通过 易位到核本地将其定位为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以靶向 这些受体和/或其下游信号传导。 PI的小组有充分的证据表明小分子和 基于肽的基于肽的抑制整联蛋白α2β1和FUS核易位的方法具有很大的 承诺在体外和动物模型中被用作抗纤维化方法。基于这些令人兴奋的结果 PI目前正在精炼预防和理想情况下停止肾脏纤维化并确定新颖的策略 通过整合素和DDR选择性调节的潜在靶向分子。 PI研究发表在高评级期刊上，包括美国肾脏学学报，肾脏 国际，矩阵生物学，临床研究杂志，仅举几例。为了成功，PI 已经组建了一组细胞生物学家，药物化学家，专家 介导的治疗分子以及大学和VA站点的肾脏病医生。 PI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末期肾脏疾病是 现役军人和退伍军人的下议院。 PI及其团队所做的工作将导致 制定新颖的策略，以阻止和理想地防止肾脏纤维化，从而提高质量 我们的退伍军人的生活。