Areas of Research

Calcium Microfluorimetry of Human Bladder Urothelial Cells

The role that bladder urothelial cells (BUC) modulate bladder function (continence and micturition) is relatively unknown at this point. Traditionally, the function of BUC have been thought of as only providing a protective role (as in any epithelium) to the underlying bladder stroma from urinary toxins/irritants. The primary determinant of bladder function has always been presented in the “neuromuscular” framework (afferent nerve provide bladder sensation, efferent nerve causes bladder smooth muscle to contract). However, this paradigm has been shifting and the proposed role of BUC now includes modulation afferent signaling of the bladder which ultimately impacts bladder continence and micturition mechanisms. Because the BUC express neurotransmitter receptors (such as purinergic receptors, muscarinic receptors, nicotinic receptors, TRP-receptors) and the BUC release neurotransmitters (such as acetylcholine, nitric oxide, ATP), BUC have a “sensor and transducer” function (as coined by Dr. Lori Birder from University of Pittsburgh). The sensor-transducer role of BUC puts the bladder urothelium front and center as a possible target in continence disorders such as idiopathic overactive bladder (OAB). We have been studying BUC sensor-transducer physiology, and specifically BUC obtained from human OAB subjects (and also asymptomatic human subjects). The video shows how human BUC can respond to a neurotransmitter (carbachol) in a dose-dependent manner. The cellular response being shown by the video is increasing fluorescence which reflect increasing intracellular calcium concentrations with increasing carbachol. Furthermore this response was augmented in OAB BUC compared to asymptomatic controls). This video is an experiment called calcium microfluorimetry. Our laboratory is on the vanguard in studying human BUC in this manner. Any animal models studying BUC function should be informed by human BUC studies, increasing translational relevance. Our laboratory seeks to be translationally relevant in order to effect a change in clinical urology in a more efficient and scientifically relevant manner.

MR-US Image Fusion for Targeted Prostate Biopsy

Prostate cancer is the most common form of malignant carcinoma and is the second leading cause of cancer-related death in men. Screening methods such as PSA has recently come under fire due to issues with specificity and the generation of false positives and overtreatment of cancers. Furthermore, traditional prostate biopsy techniques, even ultrasound guided, are taken “blind” to sites of cancer. Other imaging modalities have shown promise in the detection of nodules before metastasis, but lack clinical acceptance.
Yale has established collaboration with an Industry partner (Eigen, Green Valley CA) to establish an active surveillance protocol using MR imaging and ultrasound guided prostate biopsy. Driven by multi-parametric MR imaging, radiologist can define regions of interest before a biopsy. Using the Artemis system, the pre-procedure MRI can be fused to real-time ultrasound to allow targeted guidance of both systematic and targeted biopsy locations. This has the potential to drastically improve the ability to detect hidden cancers, and will be a corner-stone of an Active Surveillance protocol designed to mitigate instances of over-treatment in prostate cancer.

Immunohistochemical analysis of Cldn4 expression (green) in normal and malignant prostate.

Immunohistochemical analysis of biomarker expression (green) in normal and malignant prostate. (Image on Left side is Normal)

Tumor Homing Nanoparticles for Prostate Cancer Detection, Imaging and Therapies

Despite improvements in detection and treatment, prostate cancer is the second leading cause of cancer-related deaths in men, and is among the most common form of malignant carcinomas. Biochemical tests such as PSA or MR imaging are considered useful tools; however, modern studies have called into question the long-term value of PSA, and the diagnostic efficacy of imaging has yet to be determined. Therefore, novel methods to allow for greater specificity and targeting for the diagnosis of prostate cancers utilizing tumor-homing contrast agents are proposed in this work. We proposed targeting nanoparticles to the surface of prostate cancer towards the goal a cellular level contrast that can distinguish between aggressive disease and normal tissue.