PROJECT SUMMARY/ABSTRACT This Shared Instrumentation Grant supports the acquisition of the Xstrahl SARRP, a small-animal focal x-ray irradiator with cone-beam computed tomography (CBCT) for precision preclinical x-irradiation. State-of-the-art imaging and dose delivery capabilities of SARRP will enable investigators across UCSF to undertake research in diverse areas spanning from normal tissue biology to cancer therapeutics. Biomedical research into the effects of radiation exposure requires the ability to deliver ionizing radiation in a precise and conformal manner. The SARRP replicates image-guided external beam radiotherapy commonly employed to treat human cancer patients. Modern clinical x-ray radiotherapy (XRT) selectively targets the tumor while sparing surrounding normal tissue. This is achieved by coupling patient positioning using CBCT with delivery of collimated x-ray beams at multiple angles. Robust experimental models employing radiation benefit from volumetric dose calculations (volumetric dosimetry) and reproducible animal positioning systems. The SARRP incorporates these capabilities into a single platform. This proposal describes numerous research plans that will benefit from the acquisition of the SARRP, including from the three major users?Trever Bivona, MD, PhD; Jean Nakamura, MD; and William Weiss, MD, PhD ? as well as multiple additional UCSF investigators who will be major or minor users. Projects to be supported are diverse and include: (1) molecular mechanisms altering neuronal function that cause cognitive deficits after XRT; (2) effects of XRT on salivary gland regeneration in HNSCC models; (3) various combinatorial therapies with targeted XRT for glioblastoma, neuroblastoma, HNSCC, prostate, lung, and skin cancer; (4) subsequent malignant neoplasm following XRT; (5) XRT- induced metastasis and resistance to XRT; (6) biomarkers of therapeutic response to XRT; (7) synergy between thermal ultrasound therapy and XRT; and (8) lesioning brain regions of songbird involved in song learning and control in order to gain general insights into sensorimotor and vocal learning relevant to human speech acquisition. The SARRP will be housed within the Laboratory Animal Research Center barrier facility on the fifth floor of the Helen Diller Family Cancer Research Building. Principal Investigator Bruce Faddegon, PhD will be responsible for technological oversight of the equipment, ensuring correct set up and running and, together with Young Ho Seo, PhD and Jean Nakamura, MD, will assist in training users and trouble-shooting. Access to and utilization of the SARRP will be managed by the NCI- supported Preclinical Therapeutics Core (PTC) facility, which undertakes small animal preclinical therapeutic studies for UCSF scientists and affiliates (such as UC Berkeley and the Gladstone Institutes) on a fee-for-service basis. The SARRP would add to a growing list of imaging and therapeutic options available through the PTC, which has management systems in place to accommodate this acquisition.