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Funding Update for Mar 10, 2009


Protein Expression in Failing Human Hearts
Start date: Dec. 23, 2008
Expires: Nov. 30, 2010
Amount awarded to date: $193,125
Principal investigator: Margaret Westfall
Sponsor: University of Michigan Ann Arbor

The aim of this study is to "identify proteins with large scale changes in expression, and then focus on protein expression of classical protein kinase C (PKC) isoforms and proteins associated with these isoforms in failing human hearts." The study will employ a quantitative proteomic strategy to identify proteins with large-scale changes in expression using liquid-phase chromatofocusing, reverse-phase HPLC, and electrospray time-of-flight tandem mass spectrometry. Protein expression of classical PKC isoforms and associated proteins will be also analyzed by protein microarray analysis of these fractions. Results from the study are "expected to provide insight into the changes in global and PKC protein expression during human heart failure, and identify key proteins and future therapeutic targets to explore in animal models of heart failure."

Computational Framework for Analysis of Microarray Gene Expression Data
Start date: Jan. 1, 2009
Expires: Dec. 31, 2010
Amount awarded to date: $149,985
Principal investigator: Dariusz Wroblewski
Sponsor: Bioformatix

San Diego-based Bioformatix plans to "develop and validate a novel numerical framework for identification of differentially expressed transcripts, with an emphasis on analysis of experiments with small number of replicates and genes with moderate levels of expression." The approach is based on a "non-parametric method for assessment of noise distributions in microarray data, which are derived directly from the analyzed data set." According to the grant abstract, "three distinct, univariate and multivariate methods for identification of differentially expressed genes will be implemented and their results will be compared to the results of leading advanced statistical methods." In the project's phase I feasibility study, Bioformatix will analyze differential gene expression between at least nine normal tissues with varying levels of similarity, in rat and mouse. Publicly available Affymetrix data from the SymAtlas database will be also be employed. The abstract claims that the "numerical methods will be established through biological and/or experimental validation of identified genomic biomarkers using functional analysis and/or quantitative polymerase chain reaction analysis."

Discovery of Gene Expression Signatures in Cancer Stroma
Start date: Jan. 10, 2009
Expires: Nov. 30, 2013
Amount awarded to date: $307,107
Principal investigator: Robert West
Sponsor: Palo Alto Institute of Research and Education

The researchers hypothesize that "within a particular group of tumors there exist distinct types of stromal cells that affect tumor growth in different ways." They also hypothesize that soft tissue tumors, thought to be derived from different stromal precursors, function as discovery tools for the various stroma types. Based on this, the researchers propose to use STTs as "discovery tools in a genome-wide search to discover groups of novel markers that identify distinct types of tumor stroma and that recognize the normal connective tissue counterparts from which these types of stroma are derived." By identifying subsets of genes that distinguish different STTs, the project aims to examine how these gene sets can differentiate between carcinomas with distinct stroma types. The researchers plan to perform gene-expression profiling on STTs to discover further new types of carcinoma stroma. They also plan to "verify and extend our findings on tissue microarrays containing hundreds of specimens of several carcinomas from patients with known clinical follow-up." Finally, they aim to identify epithelial-stromal gene-pairs involved in the "cross-talk" between cancer and stromal cells.

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Cross-species Microarray-based Genomic Selection: Application to Nonhuman Primate
Start date: Jan. 15, 2009
Expires: Dec. 31, 2010
Amount awarded to date: $232,500
Principal investigator: James Thomas
Sponsor: Emory University

According to the grant abstract, there is a "need to develop affordable and efficient methods that use the available nonhuman primate genomic resources as a springboard for population-based genomic sequencing in a greater diversity of species." The focus of this project is to "test and to demonstrate the capability of ... microarray-based genomic selection as such a method. Specific goals include determining the capability of cross-species MGS to enrich for orthologous-targeted genomic regions of nonhuman primates at divergence levels from 1 percent to 10 percent; and demonstrating the utility of cross-species MGS for nonhuman primate and AIDS research. To do so, the researchers will apply the cross-species MGS approach toward sequencing between 125 and 250 candidate genes for the benign nature of SIV infection in the sooty mangabey, a nonhuman primate model for AIDS research that lacks genomic resources.

Multiplexed Microarray Detection of Pluripotency Related Proteins
Start date: Feb. 1, 2009
Expires: July 31, 2009
Awarded amount to date: $184,593
Principal investigator: William Patterson
Sponsor: Primorigen Biosciences

Madison, Wis.-based Primorigen will use the funds to "develop a frameless, multiplexed, microarray screening system for rapid identification and characterization of antibody matched pairs with appropriate affinity and specificity for human proteins central to pluripotency and multipotency." The core of the system is Primorigen's "frameless microarray device that allows multiplexed analysis of 96 or 384 samples against several binding targets directly on a flat array surface." This project will specifically focus on characterizing assay content for detecting eight human cell markers of pluripotency and multipotency and validating them in a multiplexed array format.

Molecular Pathways Controlling Ovarian Gene Expression
Start date: Feb. 1, 2009
Expires: Jan. 31, 2014
Amount awarded to date: $320,343
Principal investigator: Carlos Stocco
Sponsor: Yale University

This study is designed to determine the physiological role of transcription factors GATA-4 and GATA-6 in ovarian steroidogenesis, follicular development, and female fertility. The specific aims of this study are: a) to generate ovarian-specific GATA-4 and GATA-6 null mice in order to find out the explicit roles of these transcription factors in the ovary in vivo; b) to determine the effect of GATA-4 and GATA-6 deletion on ovarian cells in vitro; and c) to identify those genes that are regulated by GATA-4 and GATA-6 in fully functional ovaries in vivo using ChIP-on-chip assays. According to the grant abstract, "all the results obtained to date indicate that GATA-4 and GATA-6 may play a crucial role in the normal function of the ovary."

Interspecific divergence of Y chromosome effects on gene expression in Drosophila
Start date: June 8, 2009
Amount awarded to date: $44,846
Principal investigator: Tim Sackton
Sponsor: Harvard University

Using low-cost spotted cDNA microarrays that target the differentially expressed genes identified in this initial survey, experiments will compare different Drosophila sechellia Y chromosomes in both a D. sechellia genomic background and a D. simulans background to estimate polymorphism and divergence in gene expression, which the grant abstract terms "crucial parameters for evolutionary modeling." Using these data, models of gene expression divergence will "allow inference about the evolutionary forces that have governed the divergence of Y-linked gene expression between species." According to the abstract, "understanding how differences among Y chromosomes affect organismal phenotype is a critical first step towards understanding the potential role of the Y chromosome in human health and disease."

MicroRNA Expression and Function in Airway Epithelial Cells
Start date: Aug. 19, 2009
Amount awarded to date: $54,842
Principal investigator: Denitza Blagev
Sponsor: University of California San Francisco

The central hypothesis of this project is that microRNAs contribute to the regulation of airway epithelial gene expression during normal differentiation and allergic and inflammatory responses. The project has two specific aims: a) to determine which miRNAs are expressed in airway epithelial cells and how miRNA expression changes during differentiation and in response to IL-13, a cytokine that plays a central role in asthma; and b) to determine how airway epithelial cell gene regulation is influenced by effects of miRNAs on mRNA stability and translation. The researchers plan to survey genome-wide miRNA arrays and a "novel high-throughput reporter system" for analysis of miRNA activity. According to the grant abstract, the work could "provide new information about the expression and function of miRNAs in airway epithelial cells and may suggest new therapeutic approaches for asthma and other airway diseases."