Growth is a fundamental property of biological systems that must be exquisitely well regulated to ensure normal organismal function. The misregulation of growth contributes to a variety of diseases and disabilities, most notably obesity and cancer in which excessive cell growth and/or cell proliferation occur. Because of the fundamental nature of growth control, its core regulatory logic is likely to be conserved through evolution, enabling the use of simple, genetically tractable organisms as model systems. We have identified DBL-1 (a ligand of the TGF? superfamily related to BMP2) as a major regulator of body size in the nematode C. elegans. To elucidate the molecular mechanisms by which DBL-1 regulates growth, we have identified DBL-1 transcriptional target genes and found that these target genes include insulin growth factors and regulators of fat metabolism. These preliminary data provide the framework for an investigation into the crosstalk between insulin and TGF? signaling and its relevance to growth control. We hypothesize that DBL-1 regulates growth in part by downregulation of the insulin pathway leading to changes in fat metabolism and cell growth. To test our hypothesis, we will address the following questions: (1) Does DBL-1 regulate fat metabolism?;and (2) How are DBL-1 and insulin signaling integrated to determine organismal size? By accomplishing the aims of this project, we will uncover the regulatory interactions between insulin and TGF? signaling in vivo and their consequences for fat accumulation and growth. Our work will provide valuable information on the mechanisms of integration and crosstalk between these two highly conserved signaling pathways, providing the basis for possible intervention into growth-related disorders in humans. Additionally, this project will provide training opportunities for a graduate student and undergraduate students, who will learn current techniques in molecular biology and microscopy, as well as oral and written communication skills through lab meetings and attendance at professional conferences.
Disorders of growth pose a major public health threat facing the United States. Among these disorders, incidences of cancer and of obesity are strikingly high. This work will exploit the advantages of a simple model organism to uncover the genetic and cellular mechanisms underlying growth regulation, with the expectation of identifying potential targets for future therapies for these diseases.
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