Unraveling the Pathways Involved in Intestinal Repair After Ionizing Radiation Damage

Exposure to genotoxic environmental agents has detrimental effects on health span and aging. Macromolecular damage caused by these factors is also known to lead to diseases like cancer. Radiation therapy is the treatment of choice for malignant tumors and several non-malignant diseases. Despite its effectiveness, it often leads to unintended complications. Radio-sensitivity of healthy ‘bystander’ cells is an important factor in mediating these complications, which often result in several long-term and debilitating side effects. This incurs huge costs in patient care to maintain the well-being of survivors. Current efforts to understand the underlying molecular patho-physiology of radiation damage involve the use of in vitro human cell or rodent models. However, these methods have limitations, as in vitro models cannot perfectly mimic complex tissue micro-environments and in vivo rodent models are far too expensive, time-consuming, and restricted. To fill this critical gap, Drosophila melanogaster has been used as it is a genetically malleable and an inexpensive model to study radiation-induced damage. The conservation between humans and flies at the cellular and molecular levels allowed researchers to study similarities between flies and mammals in how they respond to radiation. DNA damage resulting from radiation exposure inhibits not only intestinal stem cell (ISC) proliferation but also causes extensive apoptosis in the enterocytes leading to increased intestinal permeability and reduced survival. To identify novel regulatory pathways that can alleviate radiation induced intestinal damage, a screen was performed using approximately strains from the Drosophila Genetic Reference Panel (DGRP). This Genome Wide Association Study (GWAS) analysis identified several candidate genes. In this thesis, two of the top candidate genes and their role in regulating intestinal damage caused by radiation were characterized. In the first aim, Meltrin was characterized for the effect of its tissue-specific knockdown in the clearance of damaged Enterocytes (EC), the main absorptive cells in fly intestine. This characterization was achieved by measuring survival, gut damage, and prevalence of apoptotic cells in irradiated guts. In the second aim, the Msi was investigated for its role in reparative proliferation of intestinal stem cells (ISCs). Results from this thesis project have identified two new conserved genes involved in radiation damage repair with potential for future relevance as therapeutic targets