University of California, Los Angeles
Grant: $885,543 - National Institutes of Health - Apr. 29, 2009
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Award Description: This proposal aims to test the hypothesis that the salivary gland pathologies in primary Sjögren's syndrome (pSS) are mediated by aberrant activities of key intracellular/intercellular networks, pathways and molecular targets. A systems approach is proposed to identify key pathways and critical molecular determinants whose values will be experimentally tested and validated. A related outcome of this project is the proof of principle of a systems approach to salivary gland pathogenesis, the ability to identify critical molecular targets and pathways. The resources (databases) and computational/modeling approaches will be made publicly available for application to other salivary gland diseases and biology. This proposal uses systems approaches, which integrate gene expression data, proteomics data and a curated Sjögren's syndrome knowledge base (SSKB), to identify disease pathways and master regulatory genes that control disease pathways in the pathogenesis of pSS. Validation of potential candidates can be supported by evidence from the SSKB. Three specific aims are in place to test the central hypothesis. SPECIFIC AIM 1: Experimental Component: To generate new, high quality transcriptomic and proteomic foundational databases of human parotid glands with normal and pSS phenotypes. SPECIFIC AIM 2: Computational/Model Building Component: Systems-biologic integration of gene expression, proteomics, and gene ontology information to identify key disease pathways and disease related hub genes. Develop a SS disease model by meta-analysis of networks and identification of key molecular targets using Weighted-Gene Co-Expression Network Analysis (WGCNA). SPECIFIC AIM 3: To Develop the Sjögren's Syndrome Knowledge Base (SSKB): A Sjögren's syndrome knowledge base (SSKB) will be built to serve as a resource for in silico validations of the SS disease model. The SSKB will be made publicly available. The completion of these Aims should lead to the identification and validation of key molecular targets in the manifestations of salivary gland pathologies in pSS pathogenesis. The stage will then be set for the validation and functional evaluation of these molecular targets in rodent models of SS for systems level analyses.
Project Description: University Medical Center Groningen (UMCG) (Arjan Vissink DMD, MD): The accrual of parotid gland biopsies from primary Sjögren's (pSS) patients fulfilling the US-EU criteria for pSS is progressing well. At this moment, under the leadership of Dr. Vissink, the UMCG group has collect parotid gland biopsies from 20 pSS patients. The targeted accrual of healthy parotid gland biopsies (controls) is expected within the next six months. Additionally, they have proposed to include parotid biopsies from pSS-like patients, which are patients with Sjögren-like complaints not fulfilling the US-EU criteria for pSS, to this project. This topic was discussed at our regular quarterly conference on June 3 2009 and was unanimously agreed that we should include this arm in our study in the validation phase. UCLA (Steve Horvath PhD): A new postdoctoral research position was created for Michael Oldham PhD as a statistical programmer. He created a new software ('RemoveOutliers:') for pre-processing gene expression data that will be used as part of this SASSP project. UCLA (David Wong DMD, DMSc): As contact PI, Dr. Wong coordinates the overall activities of this research consortium, including quarterly phone conference (June 3, 2009), a visit to Dr. Gorr on July 13 and attending a seminar on R by the new statistical programmer Michael Oldham on June 18 2009. A new postdoctoral fellow, Abu Nazmul-Hossain DDS, PhD, was hired into this project. He obtained his doctoral degree training with Kathy Moser PhD and Nelson Rhodus DDS, PhD at University of Minnesota focusing on Sjögren's syndrome pathogenesis and will be overseeing the genomic and proteomic profiling of the second set of parotid gland clinical samples to be obtained from UMCG. University of Minnesota (Sven Gorr PhD): Dr. Gorr is in the process of developing a data-base of genes and proteins involved in the autoimmune disease Sjogren's syndrome. To date, the data-base has been updated and maintained & manuscript is in preparation.
Infrastructure Description: N/A.
Jobs Summary: UCLA is a world-class educational institution in the midst of an unprecedented financial crisis that threatens our mission to provide education, research and public service benefiting millions of people. ARRA funding to the University has enabled the creation and retention of jobs to support vital scientific research and training activities that would otherwise be severely constrained or eliminated through budget cuts. The type(s) of jobs created and retained by this ARRA-fund award includes: Faculty and Investigator positions. (Total jobs reported: 3)
Project Status: Less Than 50% Completed
This award's data was last updated on Apr. 29, 2009. Help expand these official descriptions using the wiki below.
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