The objective of this research is to undertake a detailed analysis of an under-investigated class of proteins: the mammalian phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs). The functions and mechanisms of mammalian PITP function remains to be elucidated. The research plan is designed to identify mechanisms of function of specific mammalian PITP isoforms - the Class 1 PITPs. This proposal is founded on our creation and characterization of a PITP? knockout mouse and an allelic series of mice with graded defects in function of this protein. The pitp?0/0 mouse and its derivatives are attractive disease models in that these are born alive, but manifest powerful phenotypes after birth. These phenotypes permit collection of defined cell-based reagents for analysis. Using these unique animal and cellular models as primary analytical subjects, we will undertake three lines of investigation. First, we will use sophisticaed biochemical and biophysical approaches to decipher how Class 1 PITPs function at the level of single molecules. Second, we will use sophisticated and quantitative imaging and analytical assays to determine how Class 1 PITPs functionally engages signaling receptor tyrosine kinases such as epidermal growth factor receptor and platelet-derived growth factor receptor. The appropriate activity of these receptors is required for proper cell growth control and morphogen responses. Derangements lead to cancer and neurological deficits. Third, we will exploit a powerful screening platform we assembled for the purpose of identifying and validating small molecule inhibitors with high specificity for Class 1 PITPs. Such reagents would be of value as tool compounds for surgical manipulation of phosphoinositide signaling in cells, and hold the potential of identifying lead compounds for new pharmaceuticals directed at treatment of cancer or neurological deficits. PITPs play central roles in regulating signal transduction pathways that interface with diverse cellular processes. Yet, the underlying mechanisms are not understood because these have not been investigated. The Bankaitis laboratory is uniquely poised to address questions of mechanism of Class 1 PITP function as it has developed unique experimental systems for analysis.
Cancer, neurodegenerative disorders and lipodystrophies are human diseases that arise from derangements in cellular signaling processes. The first results from inappropriate cell growth, the second is a result of premature cell death, and the third reflects unbalanced metabolism. The proposed studies will help define the mechanisms by which phosphoinositide signaling pathways are regulated by a novel class of proteins in mammals - the phosphatidylinositol transfer proteins (PITPs). Essentially nothing is known about how these proteins work as molecules to execute these important signaling functions. Since PITPs, and the signaling pathways they regulate, are of direct relevance to cancer, neurodegenerative diseases and lipodystrophies, it is hoped the new and fundamental information that will derive from these studies will: (i) define a conceptual landscape for incisiv study of these proteins, and (ii) ultimately guide development of new diagnoses, or even pharmacological therapies, for neurological disorders or injuries to the central nervous system.
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