chapter  21
28 Pages

Chapter Physiological Stress Responsive Gene Regulation Systems for Tissue Targeting

Gene therapy involves the intracellular delivery of genetic materials to treat inherited or acquired diseases. Although gene therapy is not generally applied to clinical settings, it will be a clinical option for many diseases in the near future due to extensive research and development efforts. The barriers and problems experienced in developing gene therapy are being addressed by new technology. The problems include delivery-related issues such as efciency, specicity, cytotoxicity, and clearance.1 Also, gene-related issues such as the selection of appropriate genes for a certain disease, immune activation by DNA or RNA, gene expression regulation, and degradation of the gene by endogenous enzymes, should be addressed for safe and efcient gene therapy. Of these, gene expression regulation is related to the production of a therapeutic protein in a timely and localized manner.2,3

Most of the genes in our cells are expressed at a specic time and location. Without gene expression specicity, the homeostasis of the cells will be disrupted, which usually results in cell death. Therefore, cells have very sophisticated regulatory systems for gene regulation. With the advance

21.1 Introduction .......................................................................................................................... 587 21.2 Physiological States of Diseases ........................................................................................... 588 21.3 Hypoxia ................................................................................................................................. 589

21.3.1 Hypoxia-Inducible Factor-1 as a Key Regulator of Gene Expression under Hypoxia ..................................................................................................................... 589

21.3.2 Transcriptional Regulation of Gene Expression by Hypoxia ................................... 590 21.3.3 Translational Regulation of Gene Expression by Hypoxia ....................................... 591 21.3.4 Posttranslational Regulation of Gene Expression by Hypoxia ................................. 592 21.3.5 Application of Hypoxia-Specic Gene Expression Systems to Gene Therapy ........ 594

21.4 Glucose ................................................................................................................................. 594 21.4.1 Glucose-Regulated Gene Expression........................................................................ 594 21.4.2 Glucose-Inducible Promoters ................................................................................... 595 21.4.3 Glucose-Regulated Promoters .................................................................................. 596

21.5 Heat Shock ............................................................................................................................ 596 21.5.1 Heat Shock-Inducible Gene Expression ................................................................... 596 21.5.2 Heat Shock Protein Promoter-Mediated Gene Regulation ....................................... 597

21.6 Conclusions ........................................................................................................................... 598 References ......................................................................................................................................600

of molecular biology techniques, a lot of information about gene regulation has been elucidated. This information is valuable for the development of gene therapy technology, since an exogenousdelivered gene should not interrupt normal cell processes, and gene expression should be controlled by the cell condition.