Saliva performs a number of extremely important biological functions that are instrumental in maintaining oralhealth. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction(Sjogren's syndrome). Although no genes mutations have been identified that could explain the pathogenesisof Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction ofapoptosis in salivary gland acinar cells could be the two major events that could lead to salivary glanddestruction.

For genes involved in tissue generation and homeostasis, RNA polymerase II (Pol II) tends to pause immediately downstream of their transcription start sites. Compared to de novo recruitment of Pol II, a preassembled and poised Pol II could be more conducive to rapid and synchronous transcriptional activation in response to various physiologic cues. However, virtually nothing is known about the biological significance of this highly conserved and prevalent phenomenon in transcriptional regulation of tissue generation and homeostasis.

We propose to continue development and support for the UltraScan-III (US3) software suite, acomprehensive toolkit for the analysis of data from hydrodynamic experiments and hydrodynamicsimulations. Such experiments include analytical ultracentrifugation, small angle X-ray and neutronscattering experiments, as well as bead model simulations. Support for this project will assure futureavailability of a mature multi-platform analysis suite with important and unique capabilities not found inany other software packages.

We respond to PQ3 with our data showing that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumorinflammatory infiltrates. Our preliminary data show that melanoma PD-L1 regulates TIL through severalpreviously unknown tumor-intrinsic and extrinsic mechanisms. We define novel effects of tumor intrinsic PD-L1signaling on tumor proliferation, sensitivity to immune killing, in vivo growth independent of anti-tumorimmunity, and regulation of mTOR signals.

Estrogen receptor (ER)? exhibits an antitumor activity in multiple cancer types in both tumor-intrinsicand -extrinsic manners. However, little is known as to how such activity can be harnessed with high efficacyand precision, nor is it clear which host cell type(s) mediates the tumor-extrinsic function of ER?. These majorknowledge gaps hamper efforts to unleash ER? antitumor activity for cancer therapies. We recently discovereda phosphotyrosine-dependent signaling axis that controls ER? antitumor activity.

Uterine fibroids (UFs; leiomyomas) are the most important benign neoplastic threat to women's healthworldwide, but disproportionately affect women of color, particularly African American (AA) women, who have athreefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. While the underlyingcause for this risk disparity is not fully understood, recent studies implicate hypovitaminosis D as a majorcontributor.

Children with a genetic disease or birth defect are hospitalized at a younger age, stay longer, and have ahigher death rate than children hospitalized for other reasons. One in 33 infants born in the US has a birthdefect; the number one cause of infant mortality. Our long-term goal is to change these dire statistics bydelineating the mechanisms that reduce game quality by increasing mutagenesis in male gametes withincreasing age, i.e., the paternal age effect.

Awake behavior is accompanied by fluctuations in vigilance shaping the overall activity state of the brain tooptimize cellular and circuit activity. The cellular and molecular mechanisms for such brain state-dependentadjustments in neural activity are not well understood. Using a mouse locomotion paradigm we have recentlyfound that the transition from a resting state to active locomotion is associated with release of theneurotransmitter norepinephrine and leads to Ca2+ activation of astroglia.