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Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy

  • Matthew E. R. ButchbachEmail author
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 21)

Abstract

Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy—an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide—by cAMP signaling. These mathematical models not only can aid in understanding how SMN2 expression is regulated but they can also be used to examine the best ways to manipulate cAMP signaling to maximally increase SMN2 expression. These models will lead to the development of therapeutic strategies for treating SMA. This systems biology approach can also be applied to other neurological diseases, particularly those in which a disease-causing gene or a modifier gene has been identified.

Keywords

Spinal muscular atrophy Drug discovery SMN2 Ordinary differential equations Gene expression Mathematical modeling 

Abbreviations

AC

Adenylate cyclase

cAMP

Cyclic AMP

cnPDE

Cyclic nucleotide phosphodiesterase

CRE

cAMP-response element

CREB

CRE binding protein

dbcAMP

Dibutyryl cAMP

ELISA

Enzyme-linked immunosorbent assay

ESS

Exonic splicing enhancer

FL-SMN

Full length SMN

GPCR

G protein-coupled receptor

IGF1R

Insulin-like growth factor 1 receptor

ODE

Ordinary differential equation

PDE

Partial differential equation

PKA

cAMP-dependent protein kinase

PP2A

Protein phosphatase 2A

SMA

Spinal muscular atrophy

SMN1

Survival motor neuron 1

SMN2

Survival motor neuron 2

SMNΔ7

SMN lacking exon 7

SNV

Single nucleotide variant

Notes

Acknowledgments

This work was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P30GM114736) and by the Nemours Foundation.

Conflict of Interest

The author declares no conflict of interest.

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Authors and Affiliations

  1. 1.Center for Applied Clinical Genomics, Nemours Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  2. 2.Center for Pediatric Research, Nemours Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  3. 3.Department of PediatricsThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Biological SciencesUniversity of DelawareNewarkUSA

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