Bone is a major site for the preferential metastasis by advanced breast cancers. Bone metastases by breast cancers cause deadly complications and there is an unmet need for efficacious intervention with minimal side effect. The majority of previous studies have primarily focused on metastasized cancer cells or tumor supporting bone microenvironments. Here we propose to investigate the intrinsic anti-cancer metastatic potentials of the osteocytes, the most abundant bone cell type in the bone. Connexin (Cx) 43 hemichannels are richly present in osteocytes.

This proposal aims to understand mechanisms underlying B cell activation and dysregulation. It will explore the role of Rab7, a small GTPase that localizes on endosomes, in mediating NF-?B activation in normal B cells upon receptor engagement and in malignant B cells. It will also analyze the effect of Rab7 inhibition, through genetic ablation or small molecule inhibitors, in the prevention of B lymphomagenesis.

Tubule atrophy and fibrosis often develop after acute kidney injury (AKI) favoring transition to chronic kidney disease (CKD). The AKI-CKD transition has major implications, but poorly understood. We found that tubules regenerating after AKI often fail to differentiate. Such tubules are growth arrested and atrophic, and exhibit signaling that drives fibrosis. The cause of this pathology is unknown. We obtained three lines of evidence that could explain why recovering tubules become atrophic and profibrotic.

Mycoplasma genitalium (MG) is an emerging sexually transmitted pathogen that causes non-gonococcal urethritis in men and has been significantly associated with a range of reproductive tract diseases in women. Clinically, MG eradication remains a difficult task, and high rates of treatment failure indicate MG can cause persistent infection. It is unclear how MG persists in the host genital tract. Although antigenic variation has long been believed to contribute to MG persistence, this mechanism fails to explain MG persistent infection following standard antibiotic treatment.

Delaying the onset of cancer may be a viable cancer prevention strategy, but until now research efforts on this aspect are indeed limited. To this end,we are relatively advanced because our published results establish that organ specific delivery of eRapa (a novel formulation of rapamycin) can delay the development of intestinal tumors in a mouse model of familial adenomatous polyposis (FAP) and thus extended life as well as health span.

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often, the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this grant. We focus on three different channels critical to nervous function.

The long term goal of this project is to understand how presynaptic receptors, specifically GABAA and GABAB receptors, influence synaptic transmission, cellular computation, and learning in neuronal circuits. GABAA and GABAB receptors are co-expressed in the presynaptic membrane of many excitatory synapses in the central nervous system where they have been shown to modulate synaptic transmission. However, previous studies have generally studied the effects of each receptor type in isolation and with static conditions.

Our long-term goal is to determine how the aging-related breast cancer can be specifically prevented. This is an unanswered question largely because the cellular and molecular mechanisms underlying the aging-related increase in breast cancer incidence are poorly understood. We recently found that the percentage of mammary stem cells (MaSCs) in mouse mammary gland increases steadily with age.

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often, the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this grant. We focus on three different channels critical to nervous function.

The mechanistic target of rapamycin (mTOR) signaling pathway has been identified as an important and evolutionary conserved determinant of longevity in invertebrate models and mice. Rapamycin, a small molecule inhibitor of mTOR signaling, has been demonstrated as the first pharmaceutical capable of extending longevity in mice and also delaying or abrogating several age-related diseases in pre-clinical mouse models. Despite the excitement raised by these studies, their potential translational relevance in terms of preventing age-related disease in humans remains unclear.