PI: LIU, JIA Project: 1K22AI099184-01 Title: Characterization of Antiviral Functions of Steril Alpha Motif-Containing Domain Accession Number: 3399517 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== This proposed study is aimed at investigating the antiviral functions of a previously un- characterized human factor, called sterile ? motif-containing domain 9 (SAMD9). SAMD9 gene expression is up-regulated by interferons (IFNs), and is associated with apoptotic cell death in cancer cells when it is up-regulated. SAMD9 gene is highly conserved among vertebrate species, but not in lower eukaryotes, such as yeast. Recently genomic analyses showed deleterious mutations in human SAMD9 are responsible for a rare genetic disease called Normophosphatemic Familial Tumoral Calcinosis (NFTC). Patients with NFTC experience chronic inflammation early in their life, followed by the generation of calcified tumors in the ski and mucosa. Incessant pain and frequent infections are also associated with the morbidity. Although the essential role of SAMD9 during inflammatory responses has been repeatedly suggested, the biological functions of this gene remain unknown. Recent studies showed that human SAMD9 has anti-viral functions against numbers of viruses (RNA and DNA viruses). Because SAMD9 is constitutively expressed in all human cells tested, these results suggest its role as a part of host intrinsic immunity. The goal of this study is to dissect the mode of action f this protein during viral infections. First of all, through mapping the binding motifs to known virl factors that antagonize SAMD9 functions, the function domains of SAMD9 can be identified. Second, as these viruses apply different mechanisms to antagonize SAMD9's antiviral functions, results from this study will provide detail descriptions on their action using infection models by two DNA viruses, myxoma virus (MYXV) and herpes simplex virus type 1 (HSV-1). Finally and most importantly, identification of the key common cellular functions which are important to these disparate viral life cycles will be carried out. This is crucial for an in-depth understanding of human cellular innate immune mechanisms that must cope with viruses of many distinct types.
Deleterious mutations in a gene called sterile ? motif-containing domain 9 (SAMD9), cause morbidity with chronic inflammation in human, and currently there is no effective treatment for this disease. In addition, the biological function of SAMD9 as a part of human antiviral intrinsic immunity has not been completely understood. Because SAMD9 has antiviral effects against human pathogens such as Ebola and Marburg virus, understanding its antiviral functions can facilitate the discovery of new drug targets and therapeutic approaches that will lead to effective treatments to protect the general public against the threat from these harmful pathogens.