Frontotemporal disease (FTD) is a significant cause of dementia for which there is currently no effective therapy. About half of all cases are inherited and mutations in progranulin (GRN) gene account for most familial cases of FTD. The GRN gene encodes the growth factor progranulin (PGRN), which regulates cell division, survival, and migration. Also, PGRN possesses anti-inflammatory effects in the nervous tissues - potential targets for therapy. Mutations in GRN result in a functional loss of PGRN. We have employed transgenic GRN knockout (KO) mice to model FTD and to identify mechanisms leading to nerve cell death. The discovery of PGRN receptors has led to the finding that small molecules are sufficient to improve PGRN levels, alleviate inflammation, and offer the prospect of disease intervention. The discovery that PGRN binds to sortilin-1 (SORT1), a molecule that controls intracellular trafficking of proteins, heralded the first characterized PGRN receptor. This receptor is a major focus of this proposal. Collectively, the data indicate that PGRN is tightly linked with neuroinflammation and neurodegeneration and that enhanced PGRN levels in the nervous tissues may be attainable by modulation of its receptor(s) by two small, drug-like molecules (BCG#1 and BCG#5) that we have identified (IP registered with Washington University). We would like to capitalize on this success by determining the efficacy of these molecules in the test tube and in our mouse model of FTD. The overall objective of research described in this proposal is to further characterize and optimize our lead molecules that elevate PGRN levels in cellular and animal models. The results of these studies will likely lead to more effective disease-modifying small molecules and offer the prospect of potential treatment of patients with PGRN insufficiency.