University of California, Los Angeles

Grant: $389,465 - National Institutes of Health - Jul. 17, 2009

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Award Description: Identification of Genetic Modifiers of Anthrax Lethal Toxin Induced Pathophysiology Virulence of Bacillus anthracis is associated with production of a bipartite protein exotoxin called lethal toxin (LT). While our understanding of the in vitro interactions between LT and different host cells is growing rapidly, the mechanism by which LT contributes to morbidity and mortality in animals is still unclear. Here we propose to address this gap in knowledge by mapping gene(s) that influence whole-animal sensitivity to LT. To achieve this goal, we will utilize a congenic mouse strain identified in our lab that exhibits a rapid response to LT and resistance to spore challenge. In a second, complementary aim, we will determine the cellular and molecular events that give rise to the early LT-response phenotype seen in this congenic strain. The following aims are proposed.

Project Description: Aim 1: Map quantitative trait loci influencing LT sensitivity Sub Aim 1.1 Positional cloning: we will employ a positional cloning strategy to identify the number and location of quantitative trait loci (QTLs) controlling the early LT-response. We previoulsy established that at least 2 genes within a 64 Mb critical region on chromosome 11 influence the response to LT. Here, we will cross two strains of mice, B6.CAST.11M and C57BL/6J, to generate subcongenics that isolate previously identified QTLs Ltxs1, 2 and 3, which span 7 ~ 12 cM on chromosome 11. From this panel, we will determine if Ltxs2 and/or Ltxs3 contribute to the early phenotype. These mice will also be used to map other loci within the critical region on chromosome 11 that influence the disease presentation. Sub Aim 1.2 Expression QTL (eQTL) analysis: we will employ a genomics-based approach to identify genes whose expression levels change as a result of allelic variations. This information will be used to identify candidate genes corresponding to QTL(s) that modify host response to LT. We initially propose to test a single candidate gene identified by eQTL analysis for its role in host response to LT. As we further isolate subcongenic mice in Aim 1.1, additional expression QTL analyses will be performed to identify other promising candidate genes. Aim 2: Determine the Mechanism Driving the Early LT-Response Phenotype Dr. LeVine (KUMC) will define the pathological changes associated with the early phenotype in B6.CAST.11M mice. Previous evidence indicated that vessel leakage and coagulation might be key factors in the early phenotype. In addition to performing detailed analyses, we will test the hypothesis that release of soluble inflammatory mediators plays an important role in the development of these pathological features.

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. Scientific/Technical Professionals and Staff positions, such as Researchers, Post-Docs, Graduate Student Researchers, Project Managers and Statisticians. (Total jobs reported: 1)

Project Status: Less Than 50% Completed

This award's data was last updated on Jul. 17, 2009. Help expand these official descriptions using the wiki below.

Funds Recipient

University of California, Los Angeles
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Place of Performance

Los Angeles, CA 90095
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Funds from this award have been disbursed to sub-grantees. Click here to see a list of sub-grantees.

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