Mechanical loading experienced by skeletal tissues plays an important role in bone formation and remodeling.Osteocytes are the most abundant bone cell type and the major mechanosensory cells of the bone. Theyorchestrate bone remodeling from their location throughout bone matrix by coordinating osteoblastic formationand osteoclastic resorption. Osteocytes are connected to neighboring osteocytes and other bone cells via gapjunction channels and to extracellular environments via hemichannels. Both types of channels are formed byconnexin (Cx) 43.

Translating information on genetic risk for body weight regulation into molecular mechanisms can have asignificant impact on intervention and therapies. We are seeking to identify genetic variation and theirmolecular mechanisms that influences obesity through direct effects on the hypothalamus as it is the brain hubthat regulates energy homeostasis and there is now considerable evidence for genetic influence to impact thisbrain region.

Replication fork stalling and collapse is a major source of genomic instability and subsequent neoplasia. Such stressed forks can be conservatively repaired and restarted using homologous recombination (HR) repair, initiated by generating an endogenous nick at the fork junction. While there are candidate nucleases for generating this DSB, most mammalian stressed forks can be restarted without these nucleases, and the origin of this nick remains undefined.

Alzheimer's disease (AD) affects 5.5 million Americans producing cognitive deficits and mortality. Thereis no treatment for AD, thus, development of interventions to slow or reverse AD symptoms is a critical area ofresearch. Furthermore, AD is difficult to detect until substantial neurodegeneration has already occurred. Thisproposal investigates proteasome function both as an intervention to AD symptoms and as a tool for earlystage diagnosis in peripheral tissues. A key symptom of AD is proteostatic dysfunction.