Research Interests
Androgen receptor transactivation by G-protein coupled receptors in hormone-refractory prostate cancer and stimulation of prostate cancer metastasis by G-protein coupled receptors.
Integrative cardiovascular, renal and respiratory physiology and pharmacology.
The majority of my research work is currently done in collaboration with my colleague, Dr. Yaping Tu, who has had a longstanding interest in the intracellular signaling cascades that are activated when drugs or hormones bind to G-protein coupled receptors on the cell surface. Moreover, he is especially interested in the role of Regulator of G-protein Signaling (RGS) proteins in terminating these responses. His lab uses a variety of molecular biology techniques such as transfections with reporter genes or proteins with inducible expression, or the use of siRNA to suppress protein expression. The abnormal activation of androgen receptors by G-protein coupled receptors in hormone-refractory (medically incurable) prostate cancer is a focal point of research in the lab. My colleagues have shown that RGS2 is specifically down-regulated in hormone-refractory prostate cancer and that its restoration to normal levels returns the cancer to an androgen-dependent state. Our recent work has delineated the mechanisms by which vasoactive intestinal peptide (VIP) interacting with its G-protein coupled receptors leads to androgen receptor transactivation and prostate cancer cell proliferation. We are also studying mechanisms by which G-protein stimulation promotes prostate cancer metastasis, the ultimate cause of death from prostate cancer. P-Rex1, a specific activator of Rac-dependent directed cell migration, has emerged as a molecule of interest due to its activation by G-proteins and its expression in metastatic prostate cancer cell lines and biopsies. I contribute to the team effort by assisting with scientific writing, digital image acquisition and analysis when using molecular probes or assessing cell migration, and with nude mouse models of human prostate cancer tumor growth and metastasis. This is a new research focus for me that I find very exciting.
I am also currently collaborating with Dr. Peter Abel on cardiovascular research projects, and participate with him in a summer training program where I demonstrate how to set up the isovolemic Langendorff heart. With support from him and Dr. Tu, I am working to re-establish some of the other research methods and models I have developed and/or used during a research career that has been punctuated by several stops, starts, twists and turns. 
My initial training focused on the roles of alpha1- and alpha2-adrenergic receptors and their respective subtypes in cardiovascular and, especially, renal function. Dr. Abel shares my interest in the functional significance of alpha-adrenergic receptor subtypes. My publications include my work to help establish methods for reproducibly obtaining fractions of dispersed rat nephron segments enriched with proximal tubules to study these receptors in our lab, methods that were then adapted by various other labs to suit their needs. To my knowledge, I was the first person to publish methods for reproducibly measuring renal vascular reactivity in anesthetized rats with a Doppler flowprobe by cannulating the right suprarenal artery, and then using an HPLC injection port to insert precise volumes of varying concentrations of drugs into the intrarenal arterial infusion stream. I next established methods that permitted similar studies in conscious rats studied approximately 1 week after surgery, and was able to demonstrate alpha2-adrenoceptor mediated renal vasoconstriction in rats for the first time with that model. I set up an isovolemic Langendorff rat heart model to demonstrate that complement-mediated hyperacute rejection of the organ by human serum was largely due to the membrane attack complex. I subsequently established what I believe to be the first isovolemic Langendorff mouse heart model to be able to study the impact of gene knockouts and transgenes on complement mediated xenograft rejection, and also used this model to demonstrate a genetically engineered single-chain anti-C5 antibody could block this type of hyperacute organ rejection.
One of the unfortunate realities of integrative research is that it is particularly good at demonstrating the shortcomings of conclusions based entirely on in vitro experiments or untested presumptions. The publication of negative data seldom benefits a research team as a whole, and even serendipitous observations can have a detrimental impact on the team in both academic and corporate environments. Much of what I consider to be my best work was not published for these reasons and/or other financial exigencies beyond my control. For example, I demonstrated that, contrary to expectations, the abundant alpha-2 adrenergic receptors in the proximal tubule are poorly coupled to an inhibition of adenylyl cyclase. I studied regional vascular reactivity in pithed rats. (Re-establishing this high-yield model in mice is currently a high priority for me.) With my conscious rat renal vascular reactivity model, I was among the first people to find that angiotensin II vascular reactivity was selectively increased in spontaneously hypertensive rats and my pithed rat regional vascular reactivity model demonstrated that this hypersensitivity was confined to the renal vasculature. I have studied restenosis injury in the rat carotid artery in vivo to assess the effects of "sodding" regions denuded of endothelium with cultured endothelial cells; it does not work. The most technically demanding experiments that I have ever done involved assessing the role of complement components in myocardial ischemia/reperfusion injury in anesthetized mice. After 30 min of left anterior descending coronary artery occlusion and 90 min of reperfusion, the heart was harvested, perfused with stains to identify no-risk, at-risk, and dead regions, and sliced for digital image acquisition and analysis to determine the relevant heart volumes. I have used quantitative RT-PCR methodologies as indices of adrenergic receptor subtype expression and G-protein expression in microdissected mouse nephron segments. I have assisted with rat model studies assessing the reasons underlying the increased mortality rate of alcoholics, smokers, and patients with cirrhosis due to pneumococcal pneumonia. I remain very interested in most things that I have studied, and have a wide variety of untested hypotheses related to my past work. Moreover, my colleagues and I continually think of new things that we would like to test based on some of the resources that are now available to us. Reality again ultimately dictates what we can do, and right now my primary focus is prostate cancer.
Computerized acquisition of data from instrumented rats or mice, or their isolated tissues and organs, is something I began doing shortly after IBM-compatible computers were first sold. I currently use Labtech Notebook for simple data acquisition with inexpensive surplus/legacy data acquisition boards on older computers running Win 95. I also use Softwire and Visual C# with Visual Studio to program more elaborate data acquisition interfaces for Win XP.
The freedom to dream is what has always made research fun for me. Beyond this, I am a person who simply loves making things and making things work to test research hypotheses.
