BLR&D Research Career Scientist Award Application

BLR

基本信息

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
项目类别：
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

项目摘要

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.

我们研究的主要重点是探讨疾病的发展和进展机制。糖尿病肾病（DN）在20岁及以上的人群中普遍存在。在美国，退伍军人人口属于该年龄段的第六大死因。然而，近 50% 的糖尿病患者罹患糖尿病这一死亡原因并未得到充分报道。最近的一项研究表明，患有肾病的糖尿病患者患肾病的风险高出 87%。与没有肾脏疾病的患者相比，心血管死亡率的早期病理变化。 DN 尤其涉及肾小球肥大和基质蛋白（如胶原蛋白、我的实验室研究导致进展的信号转导机制。为了测试我们的概念，我们使用肾细胞（肾小球系膜细胞和近端肾小管上皮细胞）。由于高血糖的许多病理作用是在培养物以及糖尿病小鼠和大鼠模型中进行的。由转化生长因子-β (TGFβ) 介导，我们研究了该细胞因子在我们发现系膜和近端肾小管上皮细胞表达肿瘤抑制蛋白。 PTEN（10 号染色体上删除的磷酸酶和张力蛋白同源物）在糖尿病肾脏和糖尿病患者中减少近年来，我们主要研究了在高葡萄糖或TGFβ存在下培养的肾细胞。结果显示，糖尿病啮齿动物的肾细胞和肾脏中 PTEN 下调的机制。 TGFβ 参与高葡萄糖诱导的肾细胞 PTEN 水平抑制。首次证明microRNA (miR)-21、miR-26和miR-214在抑制PTEN中的作用这些研究为抗 microRNA 的新应用打开了大门。最近，我们将这些研究扩展到包括 mTOR（DN 的机制靶点）的作用。雷帕霉素）复合物 1 和 2 在糖尿病肾病中的作用我们为该要求提供了第一个证据。 mTOR 复合物 1 的专有 PRAS40 亚基失活导致肾小球系膜细胞肥大，我们与其他 VA 研究人员一起证明雷帕霉素可以改善 DN 的病理特征。糖尿病小鼠的肾脏通路然而，雷帕霉素介导的 mTOR 活性的完全抑制可能。事实上，小鼠近端肾小管上皮细胞中 mTORC1 的缺失会导致有害的临床结果。因此，最近我们关注的是一种称为 deptor 的新型蛋白质，它是一种 mTOR 复合物 1 和 2 的组成部分。事实上，deptor 是 mTOR 活性的内源性抑制剂。我们首次发现糖尿病患者的肾脏表达明显减少在糖尿病啮齿动物中，这种减少导致了 mTOR 活性的增加。高糖培养的系膜和近端肾小管上皮细胞中，deptor的表达量为减少，导致 mTORC1 和 mTORC2 显着持续激活。对于研究高血糖导致的 deptor 下调机制很重要，我们目前正在研究。糖尿病肾脏中deptor减少的表观遗传、转录后和翻译后机制此外，最近的研究表明糖尿病与肾细胞之间存在很强的相关性。此外，RCC 的发病率在 30 岁后增加，并在 6 岁达到高峰，我们发现 PTEN 的下调增加了。特定microRNA的表达有助于肾癌细胞的增殖和侵袭。因此，我们研究的目标是研究糖尿病进展的分子机制。肾病和肾细胞癌，并确定小分子药物可以靶向的信号分子基于抗 microRNA 的疗法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.