BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10364352
• 负责人: GOUTAM GHOSH CHOUDHURY
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364352
• 关键词: 18 year old; AKT inhibition; Accounting; Albuminuria; American; Applications Grants; Award; Businesses; Caring; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chromosome 10; Chronic Disease; Chronic Kidney Failure; Clinical; Collagen; Complex; Complications of Diabetes Mellitus; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Disease; Disease Progression; Down-Regulation; End stage renal failure; Enhancers; Epigenetic Process; Epithelial Cells; Event; Exhibits; FRAP1 gene; Fibronectins; Fibrosis; Follow-Up Studies; Foundations; Glucose; Goals; Grant; Grant Review; Healthcare; Homologous Gene; Human; Hyperglycemia; Hypertrophy; Individual; International; Investigation; Kidney; Kidney Diseases; Kidney Failure; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Medical; Medicare; MicroRNAs; Mission; Molecular; Monitor; Morbidity - disease rate; Mus; Outcome; PTEN gene; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Polycomb; Population; Prevalence; Proteins; Publishing; Regulation; Renal Cell Carcinoma; Renal Replacement Therapy; Renal Tissue; Renal carcinoma; Reporting; Repressor Proteins; Research; Research Project Grants; Retrospective Studies; Review Committee; Risk Factors; Rodent; Rodent Model; Role; Scientist; Signal Transduction; Signaling Molecule; Sirolimus; Study Section; System; Testing; Therapeutic; Time; Transforming Growth Factors; Translating; Trust; Tubular formation; Tumor Suppressor Proteins; Type 2 diabetic; United States National Institutes of Health; Veterans; Work; age group; aged; cardiovascular risk factor; career; cost; demographics; diabetic; diabetic patient; diabetic rat; falls; follow-up; high risk; inhibitor; innovation; kidney fibrosis; member; men; military veteran; mortality; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; pandemic disease; protein expression; response; scientific organization; therapeutic miRNA; type I diabetic

Diabetes is the number one cause of end stage kidney disease and accounts for approximately 47% of cases in the US. More than 34 million Americans have diabetes. It is prevalent in the people aged 18 years and older. The demographic of Veteran population falls in this age group. In Veterans aged 65 years and older, approximately 27% are afflicted with diabetes. A recent study demonstrated that diabetic patients with kidney disease had 87% higher risk of cardiovascular mortality. One in three patients with diabetes develop diabetic nephropathy (DN). Early pathologic changes in DN involve renal, especially glomerular hypertrophy and expansion of matrix proteins. The focus of our research is to investigate the signal transduction mechanisms that lead to the progression of DN. To test our concepts, we use both renal glomerular mesangial and proximal tubular epithelial (PTE) cells in culture and, mouse and rat models of diabetes exhibiting kidney pathologies. In kidney, high levels of transforming growth factor-b (TGFb) mediate many pathologic effects of hyperglycemia. Therefore, along with the effects of high glucose, we investigate the signaling mechanisms of TGFb in mesangial and PTE cells. We were the first to discover that high glucose decreases the expression of the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome 10) in these cells and in the renal tissues of diabetic mice and rats. We identified that this effect of high glucose is mediated by TGFb. In investigating the mechanisms, we for the first time reported that multiple microRNAs such as miR-21, miR-26 and miR-214 that are significantly increased in the diabetic kidneys regulate the hyperglycemia- and TGFb- induced inhibition of PTEN. In fact, we showed that this inhibition of PTEN expression resulted in sustained activation of Akt kinase that led to activation of mTORC1 (mechanistic target of rapamycin complex 1). mTORC1 contributes to mesangial and PTE cell hypertrophy, and expression of matrix proteins fibronectin and collagen I a2 causing renal hypertrophy and fibrosis in DN. Indeed, we showed that rapamycin ameliorated complications of DN including albuminuria in type 1 and type 2 diabetic mice. Since increased expression of above-mentioned microRNAs contribute to PTEN inhibition/Akt kinase-mediated mTOR activation, our studies opened the door to the novel application of anti-miR therapy for DN. Rapamycin-mediated complete inhibition of mTORC1 causes deleterious clinical outcome. Proximal tubular loss of mTORC1 in mice showed progressive renal fibrosis. Therefore, more recently we have focused on a novel protein, called deptor, which is a component of mTOR and is a negative regulator of both mTORC1 and mTORC2 activities. For the first time, we showed that the renal expression of deptor was significantly reduced in humans with diabetes and in diabetic rodents. This reduction contributed to enhanced mTOR activity. We also found that both high glucose and TGFb decrease the expression of deptor in mesangial and PTE cells. We identified a microRNA, miR-181a, which is increased in response to high glucose or TGFb, regulates the downregulation of deptor. More recently, we identified an independent epigenetic mechanism involving the PRC2 (polycomb repressor complex 2) component enhancer of zeste homolog 2 for high glucose-induced deptor suppression. We plan to use both these mechanisms to target the complications of DN in rodent models. Furthermore, we have identified a novel cross-talk between high glucose/TGFb and PDGFRb (platelet-derived growth factor receptor-b) activation in mesangial and PTE cells. PDGFRb inhibitor blocked hypertrophy and matrix protein expression, indicating that this can be utilized therapeutically for amelioration of DN. A strong correlation between diabetes and renal cell carcinoma (RCC) has been established. We have identified two microRNAs, miR-21 and miR-214, which are involved in DN, also contribute to the activation of mTORC1 and, proliferation and invasion of renal carcinoma cells. Thus, the goal of our studies is to investigate the molecular mechanisms of the progression of DN and RCC, and identify signaling molecules that can be targeted by small molecular drugs and anti-miR based therapies.

糖尿病是终末期肾病的头号原因，占肾脏疾病的约47%。 在美国的案例。超过3400万美国人患有糖尿病。它在18岁以上的人中很流行， 老了退伍军人人口福尔斯属于这一年龄组。在65岁及以上的退伍军人中， 大约27%的人患有糖尿病。最近的一项研究表明，糖尿病患者的肾脏 心血管疾病的死亡风险增加87%。三分之一的糖尿病患者会发展成糖尿病 肾病（DN）。DN的早期病理改变涉及肾脏，尤其是肾小球肥大， 基质蛋白的扩增。我们的研究重点是探讨信号转导机制， 导致DN的进展。为了验证我们的概念，我们使用肾小球系膜和近端 培养物中的肾小管上皮（PTE）细胞和显示肾脏病理的糖尿病小鼠和大鼠模型。在 在肾脏中，高水平的转化生长因子-b（TGF β）介导高血糖症的许多病理效应。 因此，本研究沿着高糖的作用，探讨TGF β在系膜细胞中的信号转导机制。 和PTE细胞。我们是第一个发现高糖会降低肿瘤抑制基因的表达， 蛋白质PTEN（磷酸酶和张力蛋白同源物在10号染色体中缺失）在这些细胞和肾中 糖尿病小鼠和大鼠的组织。我们发现高糖的这种作用是由TGF β介导的。在 本研究首次报道了miR-21、miR-26、miR-28、miR-29、 和miR-214在糖尿病肾脏中显著增加，调节高血糖和TGF β- 诱导抑制PTEN。事实上，我们发现这种对PTEN表达的抑制导致了持续的细胞凋亡。 Akt激酶的激活导致mTORC 1（雷帕霉素复合物1的机制靶点）的激活。mTORC1 导致肾小球系膜和PTE细胞肥大，基质蛋白纤连蛋白和胶原I的表达 a2引起DN时肾脏肥大和纤维化。事实上，我们发现雷帕霉素改善了并发症， 1型和2型糖尿病小鼠的DN包括蛋白尿。由于上述表达增加， microRNA有助于PTEN抑制/Akt激酶介导的mTOR激活，我们的研究打开了大门， 抗miR治疗DN的新应用。雷帕霉素介导的mTORC 1完全抑制导致 有害的临床结果。小鼠mTORC 1近端肾小管缺失显示进行性肾纤维化。 因此，最近我们关注了一种新的蛋白质，称为deptor，它是mTOR的一个组成部分， 是mTORC 1和mTORC 2活性的负调节剂。我们第一次发现肾脏 在患有糖尿病的人和糖尿病啮齿动物中，Deptor的表达显著降低。这种减少 有助于增强mTOR活性。我们还发现高糖和TGF β均降低了 系膜细胞和PTE细胞中deptor的表达。我们发现了一种microRNA，miR-181 a，它在细胞内表达增加。 对高葡萄糖或TGF β的反应，调节deptor的下调。最近，我们发现了一个 涉及PRC 2（polycomb repressor complex 2）组分增强子的独立表观遗传机制 zeste同源物2用于高葡萄糖诱导的依赖抑制。我们计划利用这两种机制， 针对啮齿动物模型中的DN并发症。此外，我们已经确定了一种新的串扰之间 高糖/TGFb和PDGFRb（血小板衍生生长因子受体-b）在系膜和PTE中活化 细胞PDGFRb抑制剂阻断肥大和基质蛋白表达，表明可以利用这一点 在治疗上用于改善DN。糖尿病与肾细胞癌（RCC）之间的强相关性 确立了习我们已经鉴定了两种参与DN的microRNA，miR-21和miR-214， 促进mTORC 1的活化，促进肾癌细胞的增殖和侵袭。因此，目标 本研究的目的是探讨DN和RCC发生发展的分子机制， 小分子药物和基于抗miR的疗法可以靶向这些信号分子。