The goal of this project is to understand how (B-Ras1 and (B-Ras2, members of an unusual sub-class of Ras-like proteins, are regulated, and how they in turn regulate pathways leading to NF-(B and Ral GTPases. These proteins were originally discovered through their physical interaction with the I(B( protein, and in vitro and overexpression experiments indicated that they are inhibitors of NF-(B. However the true physiological role of these proteins has remained unclear. Our preliminary results using knock-outs of both (B-ras genes shows that they act to inhibit both NF-(B and Ral GTPase pathways. Interestingly, mice lacking (B-Ras proteins also die perinatally due to defects in lung development. In this research proposal we aim to ask the following questions.
In Aim 1 we will study how (B-Ras actually regulates NF-(B. While affecting the stability of I(B( is a likely mechanism, many questions about exactly how (B-Ras functions remains unanswered. Availability of cells lacking (B-Ras will allow us to explore the underlying mechanism in a systematic manner. We will also use mice lacking (B-Ras in macrophages to study mouse models of inflammation including septic shock and collagen-induced arthritis.
In Aim 2 we will ask how (B-Ras regulates Ral, and determine whether activated Ral contributes to NF-(B activation. We will study the mechanism by which growth factor signaling disrupts the (B-Ras-RalGAP complex, and determine why binding to (B-Ras inhibits the activity of RalGAP. We will also test whether the activated Ral in (B-Ras deficient cells contributes to NF-(B activation. Finally in Aim 3 we will explore the lung phenotype seen in the (B-Ras-deficient animals. We will study the mechanism of dysregulated surfactant expression, in particular the role of NF-(B in the process. In summary these studies will provide significant new insight into the biology of these evolutionarily conserved, yet enigmatic, members of this Ras-like family of proteins.

Public Health Relevance

Chronic inflammation underlies many diseases such as arthritis, asthma and cancer. The transcription factor NF-(B plays a key role in regulating inflammation and understanding the molecular mechanism that regulates NF-(B is of great interest. In this proposal we will determine how (B-ras proteins regulate the activity of NF-(B and Ral GTPases, and determine why lack of (B-Ras leads to defects in lung development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI093985-04
Application #
8661695
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Oeckinghaus, Andrea; Postler, Thomas S; Rao, Ping et al. (2014) ?B-Ras proteins regulate both NF-?B-dependent inflammation and Ral-dependent proliferation. Cell Rep 8:1793-807
Hayden, Matthew S; Ghosh, Sankar (2014) Regulation of NF-?B by TNF family cytokines. Semin Immunol 26:253-66
Hayden, Matthew S; Ghosh, Sankar (2012) NF-*B, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203-34
Ghosh, Sankar; Hayden, Matthew S (2012) Celebrating 25 years of NF-*B research. Immunol Rev 246:5-13