Periodontal infection has been shown to increase the incidence and severity of atherosclerosis, which is now the number one cause of morbidity and mortality in the United States. Furthermore there is increasing evidence linking obesity, which is a major risk factor of atherosclerosis, to periodontal disease. In atherosclerosis, the earliest lesions contain macrophages that have phagocytized and accumulated modified lipoproteins. The continued monocyte recruitment and cholesterol accumulation in the vessel wall facilitates chronic disease progression.

Depression is a severe and common mental disorder and often coexists with metabolic disorders such as diabetes. Therefore, the identification and characterization of therapeutic targets that are potentially beneficial for the treatment of both depression and diabetes would be of great clinical significance. Adiponectin, a hormone secreted almost exclusively by white adipose tissue, is well recognized as an anti-diabetic adipokine. We have demonstrated that adiponectin insufficiency increases susceptibility to depression-like symptoms.

The arteriolar myogenic response and the venoarteriolar reflex (VAR) are local vasoconstrictor responses to increased intravascular pressure that involve local sensory afferents. Recent evidence suggests that these responses involve activation of the neuronal vanilloid receptor, TRPV1 on C-fibers causing local depolarization and neuropeptide release effects local vasoconstriction.

Transforming growth factor-beta isoforms (TGF?1, ?2, and ?3) are secreted signaling proteins. They function as immunomodulatory factors and tumor suppressors in normal and early neoplastic cells, but in many established cancers, including androgen-independent prostate cancer, they promote tumor growth and metastasis. The therapeutic benefit of antagonizing TGF? using neutralizing antibodies and small molecule receptor kinase inhibitors has been amply demonstrated in animal models of cancer, yet no inhibitors have been approved for cancer treatment in humans.

The goal of this project is to establish that protein kinase D (PKD) is a major regulator of bone formation in vivo and that attenuation of PKD activity leads to age-related osteopenia. Our published and preliminary data, as well as that of others, indicated that PKD activity is required for the in vitro differentiation and mineralizationof osteoblasts in response to bone morphogenetic proteins (BMPs) and that in aged animals there is in vitro and in vivo resistance to the bone forming actions of BMP-7.

The ultimate goal of this Program Project is to develop novel therapeutic approaches for advanced childhood sarcoma. While over 70% of children with sarcoma are considered cured, the outcome is still poor for those with advanced or metastatic disease. Specifically, the 5-year event free survival rates are 30 percent or less in children with advanced or metastatic Ewing sarcoma, osteosarcoma or rhabdomyosarcoma and intensive chemo-radiotherapy has not significantly altered this outcome.

The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of nociceptor plasticity. Dynamic changes to proteins expressed in primary afferent terminals significantly alter pain sensation. For instance, ion channel phosphorylation can modulate channel activity, thereby affecting acute nocifensive responses to noxious stimuli. However, states of persistent pain likely rely on multiple mechanisms of dynamic protein modifications to maintain peripheral nociceptor sensitization.

The applicant's career goal is to become a physician-scientist studying translational research in age- related neurodegeneration. A comprehensive training plan with a team of mentors of diverse backgrounds will ensure the applicant's career development. The proposed studies will address the mechanism of Amyloid-beta mediated mTOR dysregulation in neurodegeneration. Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and is the sixth leading cause of death in the U.S.

Methamphetamine (METH) addiction currently presents an enormous public health issue, and yet no therapeutic agent is currently approved for its treatment. Psychostimulant addiction is a chronic, progressive disease driven by numerous persistent neurophysiological adaptations. METH self-administration increases input of the neuropeptide neurotensin onto dopamine (DA) neurons in the ventral tegmental area (VTA), which are extensively implicated in drug reward processes.

Metabolic disorders including obesity, dyslipidemia and diabetes appear to be associated with monocyte dysfunction, yet the molecular mechanisms underlying monocyte dysfunction in vivo are only poorly understood. Our recent studies showed that metabolic stress promotes the dysregulation and hyper-activation of monocyte responses to chemokines and that monocyte dysfunction is a critical and rate-limiting step in the development and progression of atherosclerosis.