BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10047690
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047690
• 关键词: 1-Phosphatidylinositol 3-Kinase; 20 year old; Accounting; Age; Age-Years; American; Applications Grants; Award; Businesses; Caring; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Chromosome 10; Chromosomes; Chronic Disease; Chronic Kidney Failure; Clinical; Collagen; Complex; Complications of Diabetes Mellitus; Cultured Cells; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Disease; Disease Progression; Down-Regulation; End stage renal failure; Enzymes; Epigenetic Process; Epithelial Cells; FOXO1A gene; FRAP1 gene; Feedback; Fibronectins; Fibrosis; Foundations; Funding; General Population; Genetic Transcription; Glomerular Filtration Rate; Glomerular Mesangial Cell; Glucose; Goals; Grant; Grant Review; Healthcare; Hospitals; Human; Hyperglycemia; Hypertrophy; Incidence; Incubated; Injury; International; Investigation; Journals; Kidney; Kidney Diseases; Laboratory Study; Laminin; Lead; Longitudinal cohort study; Malignant Epithelial Cell; Malignant Neoplasms; Managed Care Programs; Measures; Mediating; Medical; Medicare; Michigan; MicroRNAs; Mission; Molecular; Monitor; Morbidity - disease rate; Mus; Outcome; Oxidative Stress; PTEN gene; PTEN protein; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phosphotransferases; Population; Prevalence; Proteins; Proteinuria; Publishing; Regulation; Relative Risks; Renal Cell Carcinoma; Renal Replacement Therapy; Renal carcinoma; Renal function; Reporting; Research; Research Personnel; Research Project Grants; Resources; Retrospective Studies; Review Committee; Risk Factors; Rodent; Role; Scientist; Seminal; Signal Transduction; Signaling Molecule; Sirolimus; Testing; Therapeutic; Time; Transforming Growth Factors; Trust; Tubular formation; Tumor Suppressor Proteins; United States; United States National Institutes of Health; Veterans; Woman; Work; age group; cancer risk; cardiovascular risk factor; care costs; care systems; career; cost; cytokine; demographics; diabetic; diabetic patient; diabetic rat; falls; follow-up; glomerulosclerosis; high risk; kidney cell; mTOR Inhibitor; mTOR inhibition; member; men; military veteran; mortality; non-diabetic; novel; pandemic disease; scientific organization; therapeutic miRNA; transcription factor

The main focus of our research is to investigate the mechanism of development and progression of diabetic nephropathy (DN). Diabetes is prevalent in the people aged 20 years and older. The demographic of veterans population falls in this age group. In the US, diabetes represents the 6th leading cause of death; however, diabetes as a cause of death is underreported. Nearly 50% of the patients with diabetes develop nephropathy. A recent study demonstrated that diabetic patients with kidney disease had 87% higher risk of cardiovascular mortality when compared with those without kidney disease. The early pathologic changes in DN involve renal especially glomerular hypertrophy and expansion of matrix proteins such as collagen, fibronectin and laminin. My laboratory studies the signal transduction mechanisms that lead to the progression of DN. To test our concepts, we use both renal cells (glomerular mesangial and proximal tubular epithelial cells) in culture and mouse and rat models of diabetes. Since many pathologic effects of hyperglycemia are mediated by transforming growth factor-β (TGFβ), we investigate the signaling mechanisms of this cytokine in mesangial and proximal tubular epithelial cells. We discovered that the expression of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted in chromosome 10) is reduced in the diabetic kidney and in renal cells cultured in the presence of high glucose or TGFβ. In recent years, we have extensively investigated the mechanism of PTEN downregulation in renal cells and in kidneys of diabetic rodents. The results showed the involvement of TGFβ in high glucose-induced suppression of PTEN levels in renal cells. Our results for the first time demonstrated the role of microRNA (miR)-21, miR-26 and miR-214 in the inhibition of PTEN expression in the diabetic milieu. These studies opened the door to the novel application of anti-microRNA therapy for DN. More recently, we extended these studies to include the role of mTOR (mechanistic target of rapamycin) complexes 1 and 2 in diabetic kidney disease. We provided the first evidence for the requirement of inactivation of the exclusive PRAS40 subunit of mTOR complex 1 for glomerular mesangial cell hypertrophy, a pathologic feature of DN. Together with other VA investigators, we showed that rapamycin ameliorated the renal pathologies in diabetic mice. However, rapamycin-mediated complete inhibition of mTOR activity may cause deleterious clinical outcome. In fact, loss of mTORC1 in proximal tubular epithelial cells of mice induces progressive fibrosis. Therefore, more recently we have focused on a novel protein, called deptor, which is a component of both mTOR complexes 1 and 2. In fact, deptor is an endogenous inhibitor of mTOR activity. For the first time, we showed that the renal expression of deptor was significantly reduced in humans with diabetes and in diabetic rodents and that this reduction contributed to the increased mTOR activity. In cultured mesangial and proximal tubular epithelial cells incubated with high glucose, the expression of deptor was significantly reduced, which resulted in sustained activation of both mTORC1 and mTORC2. Thus, it is important to study the mechanisms of deptor downregulation by hyperglycemia. We are currently investigating the epigenetic, post-transcriptional and post-translational mechanisms of deptor reduction in diabetic kidney disease. Furthermore, recent studies have demonstrated a strong correlation between diabetes and renal cell carcinoma (RCC). Also, the incidence of RCC increases after 30 years of age and peaks at the 6th decades, which fall in the demographic of veterans population. We showed that downregulation of PTEN by increased expression of specific microRNAs contributes to the proliferation and invasion of renal carcinoma cells. Thus, the goal of our studies is to investigate the molecular mechanisms of the progression of diabetic nephropathy and RCC, and identify signaling molecules that can be targeted by small molecular drugs and anti-microRNA based therapies.

本研究的主要重点是探讨骨质疏松症的发生发展机制。 糖尿病肾病(DN)。糖尿病在20岁及以上的人群中很普遍。人口统计数据 退伍军人人数在这个年龄段下降。在美国，糖尿病是第六大死因； 然而，糖尿病作为一种死亡原因的报道很少。近50%的糖尿病患者 肾病。最近的一项研究表明，患有肾脏疾病的糖尿病患者患糖尿病的风险要高87%。 与那些没有肾脏疾病的人相比，心血管疾病的死亡率。慢性阻塞性肺疾病的早期病理改变 糖尿病肾病涉及肾脏，尤其是肾小球肥大和胶原等基质蛋白的扩张， 纤维连接蛋白和层粘连蛋白。我的实验室研究导致这种进展的信号转导机制。 DN值。为了测试我们的概念，我们使用了两个肾细胞(肾小球系膜细胞和近端肾小管上皮细胞 细胞)，以及糖尿病小鼠和大鼠模型。由于高血糖的许多病理影响是 在转化生长因子β(转化生长因子β)的介导下，我们研究了该细胞因子在血管内皮细胞中的信号转导机制。 系膜和近端肾小管上皮细胞。我们发现，肿瘤抑制蛋白的表达 PTEN(10号染色体缺失的磷酸酶和紧张素同源物)在糖尿病肾脏和糖尿病患者中减少 肾细胞在高糖或转化生长因子β的存在下培养。近年来，我们进行了广泛的调查 糖尿病啮齿动物肾细胞和肾脏中PTEN下调的机制。结果显示， 转化生长因子β在高糖抑制肾细胞PTEN表达中的作用我们的结果是 首次证实了microRNA(MiR)-21、miR-26和miR-214在抑制PTEN中的作用 在糖尿病环境中的表达。这些研究为抗microRNA的新应用打开了大门 治疗糖尿病肾病。最近，我们扩展了这些研究，以包括mTOR(机械性靶点)的作用 雷帕霉素)化合物1和2在糖尿病肾病中的作用。我们为这一要求提供了第一个证据 肾小球系膜细胞肥大mTOR复合体1的专有PRAS40亚单位失活， 糖尿病肾病的病理特征。与其他退伍军人管理局研究人员一起，我们表明雷帕霉素可以改善 糖尿病小鼠的肾脏病理改变。然而，雷帕霉素介导的mTOR活性的完全抑制可能 造成有害的临床后果。事实上，小鼠近端肾小管上皮细胞mTORC1的缺失可诱导 进行性纤维化。因此，最近我们专注于一种新的蛋白质，称为Deptor，它是一种 实际上，Deptor是mTOR活性的内源性抑制因子。为 第一次，我们发现糖尿病患者肾脏中Deptor的表达显著降低。 在糖尿病啮齿动物中也是如此，这种减少有助于mTOR活性的增加。在培养中 肾小球系膜细胞和近端肾小管上皮细胞在高糖孵育后，Deptor的表达 显著降低，导致mTORC1和mTORC2的持续激活。因此，它是 研究高血糖下调Deptor的机制具有重要意义。我们目前正在调查 糖尿病肾脏Deptor减少的表观遗传学、转录后和翻译后机制 疾病。此外，最近的研究表明糖尿病和肾脏细胞之间有很强的相关性。 肿瘤(RCC)。肾癌的发病率在30岁以后增加，在60岁时达到高峰。 这在退伍军人人口中下降了。我们发现PTEN的下调是通过增加 特异性microRNAs的表达促进了肾癌细胞的增殖和侵袭。 因此，我们的研究目标是探讨糖尿病进展的分子机制。 肾病和肾细胞癌，并确定可以被小分子药物和 基于微核糖核酸的治疗。

项目成果

Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.

• DOI: 10.1016/j.cellsig.2017.09.017
• 发表时间: 2018-01
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Das F;Ghosh-Choudhury N;Kasinath BS;Choudhury GG
• 通讯作者: Choudhury GG

Nox4 is a Target for Tuberin Deficiency Syndrome.

Nox4 是马铃薯球蛋白缺乏综合症的靶标。

• DOI: 10.1038/s41598-018-21838-4
• 发表时间: 2018
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Shi,Qian;Viswanadhapalli,Suryavathi;Friedrichs,WilliamE;Velagapudi,Chakradhar;Szyndralewiez,Cédric;Bansal,Shweta;Bhat,ManzoorA;Choudhury,GoutamGhosh;Abboud,HannaE
• 通讯作者: Abboud,HannaE

microRNA-181a downregulates deptor for TGFβ-induced glomerular mesangial cell hypertrophy and matrix protein expression.

• DOI: 10.1016/j.yexcr.2018.01.021
• 发表时间: 2018-03-01
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Maity S;Bera A;Ghosh-Choudhury N;Das F;Kasinath BS;Choudhury GG
• 通讯作者: Choudhury GG