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.

糖尿病是末期肾脏疾病的第一大原因，约占47％ 在美国的案件。超过3400万美国人患有糖尿病。它在18岁的人民中很普遍， 年龄较大。退伍军人人口的人口属于这个年龄段。在65岁以上的退伍军人中， 大约27％患有糖尿病。最近的一项研究表明肾脏患者 疾病的心血管死亡风险高87％。三分之一的糖尿病患者患糖尿病患者 肾病（DN）。 DN的早期病理变化涉及肾脏，尤其是肾小球肥大和 基质蛋白的膨胀。我们研究的重点是研究信号转导机制 导致DN的进展。为了测试我们的概念，我们同时使用肾肾小球肾小球和近端 培养的肾小管上皮（PTE）细胞，糖尿病的小鼠和大鼠模型表现出肾脏病理。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作用。 因此，随着高葡萄糖的影响，我们研究了TGFB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剂的表达的人 这些细胞和肾脏中的蛋白质PTEN（磷酸酶和Tensin同源物在染色体10中删除） 糖尿病小鼠和大鼠的组织。我们确定高葡萄糖的这种作用是由TGFB介导的。在 研究机制，我们首次报道了多个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- 诱导的抑制PTEN。实际上，我们表明这种对PTEN表达的抑制作用导致了持续 Akt激酶的激活导致MTORC1激活（雷帕霉素复合物1的机械靶标）。 mtorc1 有助于肾小球和PTE细胞肥大，以及基质蛋白纤连蛋白和胶原蛋白的表达 A2导致DN的肾肥大和纤维化。确实，我们表明雷帕霉素改善并发症 DN的DN，包括1型和2型糖尿病小鼠。由于上述的表达增加 microRNA有助于PTEN抑制/Akt激酶介导的MTOR激活，我们的研究为 抗MIR治疗在DN中的新应用。雷帕霉素介导的MTORC1原因完全抑制 有害的临床结果。小鼠MTORC1的近端管状损失显示出进行性肾纤维化。 因此，最近，我们专注于一种名为Deptor的新型蛋白质，该蛋白是MTOR和MTOR的组成部分 是MTORC1和MTORC2活动的负调节剂。我们第一次证明了肾脏 糖尿病和糖尿病啮齿动物的人类的表达显着降低。这种减少 有助于增强的MTOR活性。我们还发现，高葡萄糖和TGFB都降低了 在膜和PTE细胞中表达神经区。我们确定了microRNA，mir-181a，该mirNA在 对高葡萄糖或TGFB的响应，调节了deptor的下调。最近，我们确定了 涉及PRC2（PolyComb抑制剂复合物2）组件增强剂的独立表观遗传机制 高葡萄糖诱导的抑制剂的Zeste同源2。我们计划使用这两种机制 靶向啮齿动物模型中DN的并发症。此外，我们已经确定了一个新颖的串扰 肾小球和PTE中的高葡萄糖/TGFB和PDGFRB（血小板衍生的生长因子受体-B）激活 细胞。 PDGFRB抑制剂阻断肥大和基质蛋白表达，表明可以将其用于 治疗以改善DN。糖尿病与肾细胞癌（RCC）之间有很强的相关性 已建立。我们已经确定了涉及DN的两个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 我们的研究是研究DN和RCC进展的分子机制，并确定 可以由小分子药物和抗MIR疗法靶向的信号分子。