2004 — 2006 |
Yang, Xiaoyong |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Glucocorticoid Regulation of Nf-Kb Function by O-Glcnac @ Salk Institute For Biological Studies
DESCRIPTION (provided by applicant): NF-kappaB-induced activation of proinflammatory genes can be completely repressed by the glucocorticoid receptor upon hormone binding. However, critical cofactors and mechanism that transmit the glucocorticoid signal into the NF-kappaB pathway remain elusive. We recently defined O-GIcNAc transferase (OGT) as an atypical mediator in gene repression. Hence, our first specific aim is to explore the role of this enzyme as a candidate corepressor for the glucocorticoid receptor in antiinflammatory responses. We will test a physical interaction between OGT and the glucocorticoid receptor by biochemical approaches and will examine their functional interaction by cell-based gene reporter assays. Using RNA interference, we will assess a possible role of OGT in regulating endogenous proinflammatory genes. Unlike OGT, little is known about the impact of the opposing enzyme O-Incase (OGN) on transcription. Hence, our second specific aim is to discern how these two reciprocal enzymes contribute to the activation or inhibition of the proinflammatory genetic network. Using a chromatin immunoprecipitation assay, we will study the dynamics of OGT and OGN at the promoters of either active or repressive proinflammatory genes. Moreover, we will seek to identify upstream regulators and downstream targets of these two enzymes in the transcriptional apparatus through biochemical approaches. This study is designed to delineate a precise mechanism by which O-GIcNAc regulates transcription. As glucocorticoids are currently used to treat inflammation and cancer, understanding their action via O-GIcNAc offers a new approach to treatment and drug designs.
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0.903 |
2010 — 2021 |
Yang, Xiaoyong |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
O-Glcnac Modification in Metabolic Homeostasis
Obesity has become a global pandemic that poses massive economic and public health burdens worldwide. Adipose tissue has an enormous plasticity in response to nutrient availability. Nutrient flux into the hexosamine biosynthetic pathway leads to the posttranslational modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked ?-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Our preliminary results show that deletion of OGT in mature adipocytes results in lipodystrophy and transgenic overexpression of OGT promotes diet-induced obesity. Additionally, conditioned medium from OGT-deficient adipocytes modulates preadipocyte proliferation and differentiation in vitro. To illustrate how nutrient-sensing OGT impacts adipose tissue homeostasis, we hypothesize that OGT in mature adipocytes controls adipogenesis through paracrine regulation of preadipocyte proliferation and differentiation. Aim 1 will assess in vivo adipogenesis in adipose-specific OGT knockout and knockin mice. Aim 2 will determine the effects of adipose OGT on dietary regulation of adipogenesis and whole-body metabolism. Aim 3 will identify how OGT in mature adipocytes regulates preadipocyte proliferation and differentiation in a paracrine manner. Completion of the proposed studies will define adipocyte OGT as a nutrient sensor that mediates the paracrine regulation of adipogenesis and controls the development of obesity and co-morbidities.
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0.97 |
2016 — 2019 |
Yang, Xiaoyong |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
O-Glcnac Signaling in Central Control of Energy Balance
? DESCRIPTION (provided by applicant): Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and hypertension. Induction of beige or brite adipocytes in white adipose tissue, called the browning process, promotes energy expenditure. Nutrient flux into the hexosamine biosynthesis pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N- acetylglucosamine (O-GlcNAc). It has been well established that O-GlcNAc modification of insulin signaling proteins and transcriptional regulators in peripheral tissues is important for glucose and lipid metabolism. However, little is known about the role of this sugar modification in central regulation of metabolism. Hypothalamic neurons that co-express agouti-related protein (AgRP) and neuropeptide Y (NPY) promote feeding behavior and glucose homeostasis. Our previous studies show that genetic ablation of O-GlcNAc transferase (OGT) in AgRP neurons impairs neuronal excitability, induces thermogenic gene expression in white adipose tissue, and protects mice from high fat diet-induced obesity. Our unpublished data show that OGT ablation in POMC neurons leads to decreased energy expenditure and increased adiposity. Based on these findings, we hypothesize that O-GlcNAc signaling in POMC neurons integrates nutritional and hormonal cues to regulate adipose tissue browning and energy homeostasis. The specific aims are: 1) Determine the regulation of WAT browning by OGT in POMC neurons; 2) Determine whether calcium signaling regulates OGT function in POMC neurons; 3) Determine whether O-GlcNAc signaling mediates the response of POMC neurons to metabolic cues. Completion of this proposal will reveal the importance of O-GlcNAc signaling in POMC neurons to central control of adipose tissue browning.
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0.97 |
2016 — 2020 |
Yang, Xiaoyong |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
The Role of Protein O-Glcnacylation in Liver Injury
Project Summary/Abstract The liver is a major metabolic organ responsible for maintaining whole-body homeostasis in a changing environment. Given the worldwide use of alcohol, the epidemic of obesity and viral infection, liver damage is common in clinical practice. The molecular mechanisms that control the balance between hepatocyte life and death in response to chronic liver injury remain largely elusive. O-linked ?-N-acetylglucosamine (O-GlcNAc) modification has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. This prevalent and dynamic post-translational modification is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). We recently found that liver-specific OGT knockout mice develop hepatomegaly, ballooning degeneration, and fibrosis in the liver. We therefore hypothesize that OGT acts as a critical molecular switch between hepatocyte survival and death in response to chronic liver injury. To test this hypothesis, we propose to undertake three specific aims. Aim 1 will define the role of OGT in pathogenesis of liver injury; Aim 2 will identify the critical targets of OGT in hepatocyte survival and death; Aim 3 will determine the functional importance of OGT regulation of necroptosis in liver injury. Successful completion of this project will provide critical insights into the role of OGT in regulating the balance between hepatocyte survival and death and the onset of liver injury. Detailed investigation of liver-specific OGT knockout mice will likely establish a useful mouse model that recapitulates features of human liver injury, and facilitate therapeutic target identification for prevention and treatment of chronic liver disease.
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0.97 |