User:Matthew Whiteside/Notebook/Malaria Microarray/Tasks/Task5

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TASK5: Systems biology analysis of human genes involved in malaria pathogenesis

Notes

  • This task is a continuation of Task3
  • The scope and direction of this objective is going to change (since it never really got off the ground, i am not going to define a new task, just re-use this task. See goals

Goals

  • Define key signalling pathways, complexes, proteins that are involved (or critical?) in the pathogenesis of cerebral malaria inflammation. The focus here is on the late stages of severe infection in human. Specifically, the blood stage of infection will be primary focus - this may miss protective mutations etc that eliminate malaria at earlier stages (e.g. liver)... something to consider.
  • Infection will be studied using gene expression data (microarray)
  • There is limited human malaria microarray data (see Task 4) - only one study captures human severe infection.
  • To compensate, perform meta-analysis of mouse cerebral malaria infection, identifying objectives outlined in point one. An additional objective will be to identify similarities / differences between studies.
  • Compare robust mouse data with single human study. Outline similarities and differences.

Research Question

The goals were fairly broad (this was my starting point). After looking at the datasets available, i have refined my research question for this task:

What are the key pathways, receptors and extracellular signals that trigger the downstream effects that result in CM inflammation & disease. The effects associated with or that contribute to CM are:

  • erythropetic (changes in RBC production)
  • glycolysis (changes to compensate for RBC-depletion related anemia)
  • apoptosis
  • T cell activation
  • actin rearrangement / cell motility
  • cell cycle
  • INFg activation
  • INFg response
  • complement cascade
  • cell adhesion

To answer this question, I will examine large-scale gene expression datasets from the late stages of CM infection in mice. I will compare this to a gene expression dataset of children presenting CM infection vs non-CM infected children.

A recent study compared the acute infection in humans and mice (Franklin et al.) using blood. One mouse study records early infection in brain, I could consider re-examining this aspect of infection as well.

To Do List

  1. Define studies to use in meta-analysis of mouse microarray data
    Entries
  2. Microarry normalization
    Entries
  3. Probe Annotation & LIMMA analysis

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