“Hedgehog/GLI1-mediated regulation of DNA repair in cancer, aging and neurodegenerative diseases” The overarching goal of this proposal is to identify dysregulated molecular mechanisms that contribute to age- related neuropathological conditions such as Alzheimer's disease (AD) and malignant diseases, and to develop novel preventive and treatment strategies. Similar to malignant diseases, DNA damage accumulation and mitochondrial abnormalities are elevated in aging neurons and AD patients, and may contribute to neuronal dysfunction, AD pathogenesis and progression. Our laboratory has identified aberrant upregulation of hedgehog signaling effector molecule and Glioma associate oncogene 1 (GLI1) in ovarian cancer. Its aberrant expression correlates with cancer stem cell (CSC) phenotype, chemoresistance and disease recurrence. Our preliminary data presented in the parent grant demonstrated that aberrantly upregulated GLI1 promotes expression of Fanconi anemia and breast cancer associated (FA-BRCA) DNA repair genes, including BRIP1, BRCA1, FANCD2 and RAD51 in OC. These aberrantly expressed DNA repair genes can facilitate efficient repair of DNA double strand breaks (DSB) generated by platinum based chemotherapeutic drugs, and promote acquired chemoresistance and acquisition of cancer stem cell (CSC) phenotype. Whereas, in the normal tissues GLI1 and FA-BRCA pathway plays important functions in maintaining stem cell pool, important for genomic integrity. While these DNA repair genes and pathways are mutated or dysregulated in cancers, their deficiency causes stem cell exhaustion/depletion, early onset of aging, intellectual disabilities and other age related pathologies including neurodegenerative diseases. However, studies focusing on their regulation in the brain and neuronal cells during aging and particularly in the context of neurodegenerative diseases is limited. In order to evaluate the expression of Hh/GLI1 and its dependent expression of FA-BRCA genes in the brains and neuronal cells, we have collaborated with Dr. Reddy (neuroscientist and leader in this field of aging and AD and ADRD). In this supplemental proposal, we will particularly study the GLI1 and its dependent regulation of BRCA1 interacting protein 1 or BRIP1 in the context of aging and during AD pathogenesis. Similar to OC cells and tissues, our preliminary studies identified expression of GLI1 and BRIP1 in mouse and human brains. Interestingly, expression analysis indicates diminished levels of BRIP1 transcript and protein levels in aging and AD mouse brains. BRIP1 is one of the Fe-S cluster, and DEAH domain containing 5’ to 3’ DNA helicases also mutated in Fanconi anemia (also known as FANCJ) genome instability syndrome with progressive bone marrow failure and malignant diseases at early in life. BRIP1 functions were reasonably well studied in DNA repair, however, there is limited data on its role and regulation during aging and neurodegenerative diseases. BRIP1 is highly expres...