The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathwayof DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment ofnucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has beenshown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities ofBRCA1 can be reconciled in HR repair.

Most BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells.BRCA1 plays important roles in double strand break (DSB) repair and response to DNA replication stress.However, it remains a conundrum as to whether these ubiquitously important functions of BRCA1 are sufficientto account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnectcould inform more effective risk assessment and disease prevention.

The mTORC1 pathway regulates multiple cellular processes to promote a switch from catabolic toanabolic metabolism and is thus under tight regulatory control by growth factor signaling and nutrientsensing pathways. Dysregulation of this complex machinery is implicated in many cancers, so definingthe key mechanisms by which mTORC1 senses changes in cellular homeostasis to activate growthsignals is of great relevance. Spatial regulation of mTORC1 signaling has been recognized as a majormechanism that influences the cellular response to nutrients and the lysosome is central to thisprocess.

This competing renewal of our longitudinal project proposes to elucidate mechanisms driving the initiationand progression of substance use is consistent with NIDA and NIMH's recently outlined strategic plans (NIDA,2016; NIH CRAN, 2015; NIMH, 2015) prioritizing research on the period between adolescence and youngadulthood. Defining features of typical adolescent development are increases in sensation seeking followed bymore gradual increases in impulse control (described by the Dual Systems model).

The purpose of this K23 application is to support my short-term career objectives of acquiring multimodalneuroimaging, neurocomputational, biostatistical, and theoretical social cognitive knowledge in the study ofanxiety and emotion regulation in youth at high-risk for bipolar disorder (BD). Longitudinal evidence suggeststhat youth at high-risk for BD that develop any mood disorder experience an anxiety disorder as an earlyantecedent. Anxiety is therefore an important symptom in the developmental trajectory of BD.