BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10512762
• 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/10512762
• 关键词: 18 year old; Accounting; Albuminuria; American; Applications Grants; Award; Businesses; Caring; Categories; Cells; 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; Invaded; Investigation; Kidney; Kidney Diseases; Kidney Failure; 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 Receptor; Polycomb; Population; Prevalence; Proliferating; 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; care seeking; 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

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.

糖尿病是导致终末期肾病的第一大原因，约占终末期肾病的 47% 美国的案例。超过 3400 万美国人患有糖尿病。流行于 18 岁以下人群 年纪大了。退伍军人人口属于这个年龄段。在 65 岁及以上的退伍军人中， 大约 27% 患有糖尿病。最近的一项研究表明，糖尿病患者的肾脏 疾病导致心血管死亡的风险增加 87%。三分之一的糖尿病患者患有糖尿病 肾病（DN）。 DN 的早期病理变化涉及肾脏，特别是肾小球肥大和 基质蛋白的扩张。我们研究的重点是研究信号转导机制 导致 DN 进展。为了测试我们的概念，我们使用肾小球系膜和近端肾小球 培养中的肾小管上皮（PTE）细胞以及表现出肾脏病理的糖尿病小鼠和大鼠模型。在 肾脏，高水平的转化生长因子-b (TGFb) 介导高血糖的许多病理效应。 因此，除了高血糖的影响外，我们还研究了 TGFb 在系膜细胞中的信号传导机制。 和 PTE 细胞。我们是第一个发现高葡萄糖会降低肿瘤抑制因子表达的人 这些细胞和肾脏中的蛋白质 PTEN（10 号染色体中删除的磷酸酶和张力蛋白同源物） 糖尿病小鼠和大鼠的组织。我们发现高葡萄糖的这种作用是由 TGFb 介导的。在 为了研究其机制，我们首次报道了多种microRNA，例如miR-21、miR-26 和 miR-214 在糖尿病肾脏中显着增加，调节高血糖和 TGFb- 诱导 PTEN 的抑制。事实上，我们发现 PTEN 表达的这种抑制导致了持续的 Akt 激酶的激活导致 mTORC1（雷帕霉素复合物 1 的机制靶标）的激活。 mTORC1 有助于系膜和 PTE 细胞肥大，以及基质蛋白纤连蛋白和 I 型胶原蛋白的表达 a2导致DN肾肥大和纤维化。事实上，我们证明雷帕霉素可以改善并发症 DN，包括 1 型和 2 型糖尿病小鼠的蛋白尿。由于上述表达增加 microRNA 有助于 PTEN 抑制/Akt 激酶介导的 mTOR 激活，我们的研究为 抗 miR 疗法在 DN 中的新应用。雷帕霉素介导的 mTORC1 完全抑制导致 有害的临床结果。小鼠近端肾小管 mTORC1 缺失显示进行性肾纤维化。 因此，最近我们重点关注一种称为 deptor 的新型蛋白质，它是 mTOR 的组成部分， 是 mTORC1 和 mTORC2 活性的负调节因子。我们首次证明肾 在患有糖尿病的人和糖尿病啮齿动物中，deptor 的表达显着降低。此次减持 有助于增强 mTOR 活性。我们还发现高葡萄糖和 TGFb 都会降低 deptor 在系膜细胞和 PTE 细胞中的表达。我们发现了一种 microRNA，miR-181a，它在 对高葡萄糖或 TGFb 的反应，调节 deptor 的下调。最近，我们确定了一个 涉及 PRC2（多梳阻遏复合物 2）成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 deptor 抑制。我们计划使用这两种机制 针对啮齿动物模型中 DN 的并发症。此外，我们还发现了一种新颖的串扰 系膜和 PTE 中的高葡萄糖/TGFb 和 PDGFRb（血小板衍生生长因子受体-b）激活 细胞。 PDGFRb 抑制剂阻断肥大和基质蛋白表达，表明可以利用它 治疗上改善 DN。糖尿病与肾细胞癌 (RCC) 之间存在很强的相关性 已成立。我们已经鉴定出两种参与 DN 的 microRNA，miR-21 和 miR-214， 有助于mTORC1的激活以及肾癌细胞的增殖和侵袭。因此，目标 我们研究的主要目的是研究 DN 和 RCC 进展的分子机制，并确定 可以被小分子药物和基于抗 miR 的疗法靶向的信号分子。