Catherine Moore, PhD - US grants

DESCRIPTION (provided by applicant): The normal function of the SDF-CXCR4 axis during development of the immune response, is to mediate migration of select hematopoietic, neuronal, and/or cardiovascular cells. The abnormal acquisition of functional CXCR4 receptors in several cancers, unmasks an ability of non-motile tumor cells to migrate and invade into SDF-expressing organs. These processes promote metastasis, the major cause of mortality in cancer patients. Therefore, developing strategies for CXCR4 inhibition are of great interest. In addition to the development of small molecule antagonists and neutralizing antibodies, vigorous attempts have been made to identify therapeutic targets that are required for CXCR4-mediated metastasis. We recently identified ARF6, a monomeric G protein of the Ras superfamily, as a novel regulator of CXCR4 trafficking and signaling. The proposed research specifically addresses an ARF6 requirement for CXCR4 functions which are dependent on SDF gradient sensing, including directional motility and differential signaling kinetics. This research will provide mechanistic insight into the acquisition of a metastatic phenotype, and will advance the establishment of ARF6 as a novel therapeutic target in aggressive CXCR4-expressing cancers. Aberrant CXCR4 expression was initially identified in breast carcinoma. However, CXCR4 has now been shown to be dysregulated in up to 23 different cancers including prostate carcinoma, melanoma, and neuroblastoma, greatly broadening the implications and future directions of the proposed research. Notably, breast and prostate carcinoma currently have the highest incidence and the second highest mortality rates. PUBLIC HEALTH RELEVANCE: The proposed research will significantly advance the establishment of a novel cancer therapeutic target, and provide mechanistic insight into the process of metastasis. Metastasis is the major cause of mortality in cancer patients. Therefore, this research will impact cancer-related health conditions.

ABSTRACT Compulsive eating behavior, an underlying transdiagnostic construct of eating disorders and some forms of obesity, affects an estimated 15 million adults in the United States. Negative reinforcement, or performing a behavior (i.e. overeating) to alleviate a negative emotional state, is conceptualized as a key construct of compulsive eating as well as compulsive drug use. Diminished reward sensitivity is thought to contribute to the negative emotional state driving the negative reinforcing effects of palatable food, but causal neurobiological mechanisms are poorly understood. Recent evidence indicates a key role of the corticotropin releasing factor (CRF) system in the ventral tegmental area (VTA) in downregulation of dopamine systems in animal models of addiction, and this brain stress system is upregulated in the VTA by drugs of abuse. Additionally, the upregulation of the CRF-CRF1 system in the VTA is implicated in driving drug self-administration, escalation of intake, and relapse. In a model of compulsive eating, we have shown that intermittent palatable diet access results in decreased reward sensitivity, increased oral intake of d-Amphetamine, and increased CRF in the VTA. The primary objective of this application is to uncover functional reward circuitry adaptations induced by palatable diet cycling that contribute to reward deficits, compulsive eating, and susceptibility to drug taking. We hypothesize that palatable diet cycling causes reward deficits through a CRF-dependent mechanism in the VTA, where recruited CRF dampens dopaminergic release. A secondary objective is to compare male and female rats on palatable diet cycling induced reward deficits, subsequent susceptibility to drug self- administration, and modulation of these effects by the CRF system. Thus, in Aim 1, we will examine reward system functioning in male and female palatable diet cycled rats, by measuring sensitivity to the reward enhancing effects of d-Amphetamine using intra-cranial self-stimulation (ICSS) procedures. To then determine susceptibility to self-administer drugs of abuse, we will investigate intravenous (IV) d-Amphetamine self- administration, a more reliable method of drug self-administration in animals that avoids the confound of oral ingestion. In Aim 2, we will use viral-mediated CRF-1 receptor gene knockdown in the VTA of TH-Cre rats to examine the role of the CRF-CRF1 system on overconsumption of palatable food in the first hour of renewed access, d-Amphetamine-evoked dopamine release (in vivo microdialysis), reward system functioning (ICSS), and IV drug self-administration. The goal of these experiments is uncovering functional reward circuitry adaptations induced by palatable diet cycling that contribute to reward deficits and addictive-like behaviors. These proposed experiments have potential to unravel the mechanisms linking the brain reward and stress systems in compulsive eating and other addictions with implications for pharmacotherapeutic treatments.