G protein-coupled receptors (GPCRs) are a family of proteins expressed in the brain which play important roles in numerous neuronal functions including cognition, mood, appetite, pain, and synaptic transmission. In the context of AD, GPCRs are associated with multiple stages of β-amyloid precursor protein (APP) proteolysis, including modulation of the α-, β-, and γ-secretase processing of APP, and in regulation of Aβ degradation and Aβ-mediated toxicity. Collectively, studies indicate an intimate association between GPCRs and the amyloid pathway in AD; however, the true molecular nature of these relationships remains at best only partially understood.
We identified the orphan GPCR GPR3 as a modulator of the γ-secretase-mediated processing of APP in vitro and in vivo in AD transgenic mouse models. We also determined that the expression of GPR3 is elevated in a subset of sporadic AD patients. To gain further understanding of the mechanism of the GPR3-mediated effect on the γ-secretase complex and Aβ generation, we determined that classic GPCR activation of heterotrimeric G proteins and consequent downstream signaling was not involved in the observed effect on Aβ levels; however, a small family of GPCR regulatory proteins known as the β-arrestins, which initiate signaling events with unique cellular and physiological or pathophysiological consequences, are involved in the regulation of Aβ levels via two GPCRs, the β2-adrenergic receptor and GPR3. We also determined that the expression of β-arrestin 2 is elevated in the human AD brain. These observations have potentially tremendous cell biological and therapeutic implications that could contribute fundamental insight into understanding GPCR dysfunction in AD.
The major research interests of the laboratory focus on elucidation of the pathogenic mechanisms of GPCR dysfunction in AD. Specifically, a multidisciplinary approach, combining mouse genetics with cellular and biochemical techniques, imaging, and behavioral studies, is employed to investigate the pathogenic cascade leading to neurodegeneration. We are looking for postdoctoral candidates who are interested in understanding GPCR and β-arrestin regulation of Aβ generation under physiological and pathophysiological conditions and exploring the therapeutic potential of GPCR/β-arrestin-dependent signaling complexes in AD.
Qualifications:
- A recent Ph.D. in neuroscience, biology, biochemistry or related field is required.
- Proficiency in molecular and biochemical approaches is required.
- Experience with cell and neuronal cultures are required.
- Experience with mouse handling, including injection, dissection, and behavioral approaches, is preferred.
- Immunocytochemistry and immunohistological techniques for bright-field and confocal microscopy is preferred.
- Experience with optical and electrophysiological approaches is preferred.
- Excellent verbal and written communication skills, technical expertise, and scientific creativity are essential.
Interested individuals should send a detailed CV with bibliography, a brief statement of research accomplishments and future interests (maximum of one page), and three strong letters of recommendation to amantha@pitt.edu. The position is available immediately.
Amantha Thathiah, PhD
Assistant Professor, Neurobiology
University of Pittsburgh
Office: (412) 383-4078
Fax: (412) 383-5267