Grants and Contracts Details
Technical Abstract: Accumulating evidence suggests that the Prader-Willi syndrome is caused by the loss of snoRNA (small nucleolar RNA) expression. We propose a collaboration between two groups that aims to identify substances that can substitute the loss of one of these snoRF4As. In published and preliminary studies, one group demonstrated that one of this snoRNA, HBII-52, regulates pre-mRNA splicing of at least seven different genes. Two of these genes, the serotonin receptor 5-HT2C and the corticotrophin releasing hormone receptor could be a molecular link to the eating disorders and central adrenal insufficiency observed in people with Prader-Willi syndrome. To identify substances that change wrong splice site selections that are observed in an increasing number of diseases, the co-PI set up a high- throughput screening system that was successfully used to identify substances that regulate splice site selection in the tau gene. In the first aim, we propose to apply this screening system to identify substances influencing alternative splicing of the serotonin receptor 5-HT2C and the corticotrophin releasing hormone receptor. Identified substances will be verified for their ability to change splice site selection of the endogenous genes, the time course of their action and their toxicity. To gain more insight into the mechanism of splicing regulation, we propose in the second aim to identify splicing factors that regulate splice site selection of the seven genes that are dependent on HBll-52. This work will show which factor(s) are recruited by HBII-52 to regulate splice site selection and which substance(s) can substitute for the loss of HBII-52. Lay Abstract and Relevance Statement: Genetic studies strongly indicate that the Prader-Willi syndrome is caused by the loss of small nucleolar RNA5 (snoRNA). SnoRNAs are short RNAs that do not encode a protein. In most cases studied, snoRNAs help in the modification of other RNAs. However, the function of the snoRNAs missing in people with Prader-WiHi syndrome is not clear. In published and preliminary data we showed that one of these snoRNAs, 1-1811-52, regulates pre-mRNA splicing of at least seven genes. Pre-mRNA splicing is the process that makes mature mRNAs out of their precursors. Most pre-mRNAs are alternatively spliced, as several different molecules are made from a single precursor molecule. MRNAs contain the information to produce proteins and the alternative splicing process allows to make different proteins from a single precursor pre-mRNA. Our findings indicate that the snoRNAs missing in Prader-Wiui syndrome regulate which proteins are made from at least seven different genes. In a collaborative project, we propose to identify substances that regulate the splicing pattern of two pre-mRNAs that are regulated by a snoRNA missing in people with Prader-Willi syndrome. The two mRNAs, the serotonin receptor and corticotrophin releasing hormone receptor are potentially involved in eating disorder and central adrenal insufficiency observed in the Prader-Willi syndrome. We will use a recently established and working screening system to identify substances that have an effect on alternative splicing that is similar to the effect the HBII-52 snoRNA has. Most of the substances that we will be testing have FDA approval or are under FDA consideration. Several drugs are known to act on distinct splicing regulatory proteins. We will therefore determine what other regulatory proteins could substitute for the loss of HBII-52, with the aim to test then drugs that have been shown to regulate these splicing bctors in other systems. This work is relevant for the mission of FPWR, as it could identify drugs that modulate the function of genes that are important for eating disorger and central adrenal insufficiency observed in the Prader-Willi syndrome. These drugs could be further tested in cell and mouse models and could be a first step towards a therapy.
|Effective start/end date||7/1/09 → 6/30/10|
- Foundation for Prader Willi Research: $45,000.00
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