OKHSC COBRE: UBIQUITIN IN HYPERGLYCEMIA-INDUCED MESANGIAL CELL HYPERTROPHY

OKHSC COBRE:泛素在高血糖引起的系膜细胞肥大中的作用

基本信息

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic nephropathy is a major complication of diabetes and the leading cause of end-stage renal disease. The earliest morphological changes accompanying diabetic nephropathy are hemodynamic and structural changes in the renal glomerular and tubular compartments. At the cellular level, hypertrophy of the mesangial cells is a hallmark of these early changes. Multiple lines of experimental evidence have revealed a prominent role for the interplay of the angiotensin II receptor type 1A (AT1 A) and p27Kip1 in diabetic mesangial cell hypertrophy. p27Kip1 is a cell cycle inhibitor that normally must be degraded to enable progression from G1 to S phase. During hyperglycemia, p27Kip1 is inappropriately stabilized through signaling events from the AT1 A. An effector of the AT1A called RCBTB1 is required for the induction of cellular hypertrophy, but the function of RCBTB1 and how it contributes to hypertrophy following hyperglycemia are unknown. We have discovered that RCBTB1 is a component of the ubiquitin system and that the same domain of RCBTB1 that binds to the AT1A also interacts with UBE2E3, a ubiquitin conjugating enzyme. Our hypothesis is that UBE2E3 and RCBTB1 modulate the AT1A in a ubiquitin-dependent fashion to contribute to p27Kip1-dependent, mesangial cell hypertrophy. Our model system is rat mesangial cells, a well-characterized glomerular cell model that recapitulates the hypertrophy observed in diabetic nephropathy. Our specific aims are: (1) to biochemically map the complexes formed between the AT1 A, RCBTB1, and UBE2E3, and (2) to determine if disrupting the expression/function of RCBTB1 and UBE2E3 alters p27Kip stabilization and cellular hypertrophy in response to high glucose. These studies will be done in tissue culture cells and complemented by studies in an STZ-rodent model of diabetic nephropathy. Kidneys from these animals will be analyzed histologically, immunohistologically, and biochemically for hypertrophy and p27Kip1 accumulation. To complement these aims, we will generate mice null for UBE2E3 or RCBTB1. These animals will provide us with powerful tools to study UBE2E3 and RCBTB1 by genetic and physiological methods in validated animal models of diabetic disease. Collectively, the information learned from these studies may contribute to the rational design of new treatment options for diabetic nephropathy. Such therapies are desperately needed as the incidence of diabetes and renal failure escalate
这个子项目是众多研究子项目之一

项目成果

期刊论文数量(0)
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Scott M Plafker其他文献

Scott M Plafker的其他文献

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{{ truncateString('Scott M Plafker', 18)}}的其他基金

Interrogating the intersection between diet and ocular autoimmunity
探究饮食与眼部自身免疫之间的交叉点
  • 批准号:
    10419170
  • 财政年份:
    2022
  • 资助金额:
    $ 21.61万
  • 项目类别:
Interrogating the intersection between diet and ocular autoimmunity
探究饮食与眼部自身免疫之间的交叉点
  • 批准号:
    10597231
  • 财政年份:
    2022
  • 资助金额:
    $ 21.61万
  • 项目类别:
Treatment strategies for autoimmune demyelinating optic neuritis
自身免疫性脱髓鞘性视神经炎的治疗策略
  • 批准号:
    9249047
  • 财政年份:
    2016
  • 资助金额:
    $ 21.61万
  • 项目类别:
OKHSC COBRE: THE ROLE OF THE UBIQUITIN SYSTEM IN RETINAL DEGENERATION
OKHSC COBRE:泛素系统在视网膜变性中的作用
  • 批准号:
    8360280
  • 财政年份:
    2011
  • 资助金额:
    $ 21.61万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8727042
  • 财政年份:
    2011
  • 资助金额:
    $ 21.61万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8536839
  • 财政年份:
    2011
  • 资助金额:
    $ 21.61万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8106682
  • 财政年份:
    2011
  • 资助金额:
    $ 21.61万
  • 项目类别:
Control of redox regulators by the ubiquitin system
泛素系统对氧化还原调节剂的控制
  • 批准号:
    8320952
  • 财政年份:
    2011
  • 资助金额:
    $ 21.61万
  • 项目类别:
OKHSC COBRE: PROTECTING THE RETINA FROM OXIDATIVE STRESS
OKHSC COBRE:保护视网膜免受氧化应激
  • 批准号:
    8167973
  • 财政年份:
    2010
  • 资助金额:
    $ 21.61万
  • 项目类别:
OKHSC COBRE: UBIQUITIN IN HYPERGLYCEMIA-INDUCED MESANGIAL CELL HYPERTROPHY
OKHSC COBRE:泛素在高血糖引起的系膜细胞肥大中的作用
  • 批准号:
    7721020
  • 财政年份:
    2008
  • 资助金额:
    $ 21.61万
  • 项目类别:

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