Lauren Baker, DVM, PhD
Dr. Baker is an Assistant Scientist in the School of Veterinary Medicine and the Department of Urology, School of Medicine and Public Health. Her mentors are Dr. Corinne Engelman and Dr. Stephen Nakada.
The title of Dr.Baker’s research is Discovering genetic drivers of calcium oxalate urinary stone disease through multi-omics dissection in the spontaneous dog model. Kidney stone disease is a common, life-altering diagnosis causing significant patient morbidity. Over 75% of kidney stones are composed of calcium oxalate (CaOx), and recurrence is common. Genetic predisposition plays a large role in disease initiation. The complexity of the disease and human genetic diversity have limited the success of genetic studies in human beings.
The Miniature Schnauzer dog is an excellent spontaneous animal model for genetic study of CaOx urinary stones. Miniature Schnauzers are 12 times more likely to develop CaOx stones compared to the general canine population, and reduced genetic diversity within the breed increases statistical power to detect genetic associations. Previous epidemiological research shows that the majority of Miniature Schnauzers with CaOx stones are hypercalciuric, which is the most common metabolic abnormality in humans. One third of these dogs also have disorders of vitamin D metabolism, indicating that there are multiple drivers of hypercalciuria within the breed. Therefore, the dog model provides the advantage of reduced genetic complexity while maintaining disease complexity that is applicable to the human condition.
Aim 1 of Dr. Baker’s work will pursue the complexity of CaOx stone disease through metabolomics analysis to define molecular phenotypes before genetic association analysis to discover genetic drivers of metabolic abnormalities. Aim 2 will follow up on preliminary evidence that a long intergenic non-coding RNA (lincRNA) is driving regulation of the calcium sensing receptor (CASR), causing absorptive hypercalciuria in stone formers. This work will expand this analysis to discover additional RNA biomarkers, and utilize network analysis to define core genes and genetic pathways that are involved in disease pathogenesis. A similar RNA sequencing analysis in human beings will be performed to construct a consensus network to formally define genes and genetic pathways that are shared between dogs and humans, which will guide future research. View Dr. Baker’s CV
Matthew D. Grimes, MD
Dr. Grimes is an Assistant Professor (CHS) in the Department of Urology at the School of Medicine and Public Health. His mentors are Drs. Wade Bushman and Chad Vezina.
The title of Dr. Grimes’ work is loss of CD44 expression drives altered collagen structure in lichen sclerosus. Lichen sclerosus (LS) is a poorly understood chronic inflammatory condition of the genital skin with an estimated prevalence of 1:300. Approximately 20% of men with LS develop urethral stricture disease (USD). These patients commonly develop profound fibrosis of the entire anterior urethra requiring complex and morbid surgical reconstruction with low success rates. The mechanisms by which LS leads to USD are unknown and represent a critical knowledge gap in benign urology.
Dr. Grimes’ long-term career goal is to develop minimally invasive and nonsurgical treatments of LS and USD through improved understanding of its molecular pathogenesis. This proposal focuses on the principal hyaluronic acid receptor CD44. Human LS skin lesions are characterized by a loss of CD44 and an overabundance of extracellular hyaluronic acid. Lichen sclerosus skin lesions and associated stricture are characterized by prominent collagen fibrosis in the extracellular matrix. A mouse model of genetic epithelial CD44 depletion recapitulates this pattern of increased hyaluronic acid abundance and collagen fibrosis. The proposed research plan will directly test the overarching hypothesis that loss of CD44 expression in patients with lichen sclerosus triggers extracellular hyaluronic acid accumulation, TGF-β pathway activation, and collagen accumulation.
While conducting this work, Dr. Grimes will complete a Certificate Program in the Foundations of Clinical Research and be mentored by a diverse team with expertise in advanced microscopy, image analysis, and utilization of transgenic animal and in vivo functional testing to link molecular mechanisms to physiological outcomes. The proposed research will provide preliminary data for a subsequent K23 application, and the proposed training plan will prepare Dr. Grimes to achieve his long-term goals as an independent researcher. By defining the mechanisms driving fibrosis in LS he will identify putative therapeutic targets and alter the current “surgery first” treatment of LS and related USD. View Dr. Grimes’ CV
LaTasha Crawford, VMD, PhD, Diplomate American College of Veterinary Pathologists
Dr. Crawford is an Assistant Professor in the School of Veterinary Medicine and Department of Patholbiological Sciences. Her mentors are Drs. Dale Bjorling and Chad Vezina.
Dr. Crawford’s research focuses on chronic pain. Chronic pain associated with urologic disease affects millions of people in the U. S. alone, yet is exceedingly challenging to treat. There is an unmet therapeutic need that extends beyond the opioid crisis, as many existing therapies often lead to addiction, cause unwanted side effects, or prove inadequate for managing pain in many patients. Deficits in the ability to diagnose or effectively treat pain patients stem from a lack of understanding of pain mechanisms; this is particularly true for bladder pain. For example, in interstitial cystitis, it is still unknown what causes pain symptoms and why comorbid disease in other organ systems is so frequent. Recent studies indicate that many patients with bladder disease have comorbid changes in somatosensory neurons that are diagnostic for neuropathic pain. This suggests that somatosensory neurons may play a role in referred pain, challenging the existing dogma that referred somatic pain is due to spinal cord mechanisms. Somato-visceral crosstalk within the peripheral nervous system comprises a substantial gap in our knowledge of bladder pain mechanisms. Dr. Crawford’s research will test the hypothesis that there is peripherally-mediated crosstalk between somatosensory and bladder sensory neurons that contributes to comorbid pain in distinct organs systems and provides a mechanism for dysregulation of bladder function. To test this hypothesis, she will determine the cell type-specific molecular, anatomic, and neurophysiologic underpinnings of somato-visceral crosstalk in mouse models of cystitis and hindlimb nerve injury. This project will optimize an innovative neurophysiology approach, provide experience in transcriptomics, and develop Dr. Crawford’s expertise in biomarkers of bladder pain, propelling her career as a clinician-scientist. Her findings will have significant benefits for urologic disease research by highlighting potential diagnostic features of comorbidities in bladder pain patients and providing a mechanistic rationale to guide selection of existing anti-pain therapies as well as development of novel therapeutics. View Dr. Crawford’s CV
Petra Popovics, PhD
Dr. Popovics is an assistant scientist in the School of Veterinary Medicine and the Department of Urology, School of Medicine and Public Health. Her mentors are Drs. Will Ricke and Chad Vezina.
Dr. Popovics`s research focuses on identifying the role of osteopontin in prostatic inflammation and fibrosis. Approximately one in every four men aged 50 or above develop lower urinary tract symptoms (LUTS) that significantly affects the quality of life of these patients and represents an economic burden on the US health care system. LUTS have long been thought to be primarily instigated by benign prostatic hyperplasia (BPH), however, associated symptoms may also develop in the absence of significant prostatic enlargement. There is increasing evidence showing that chronic prostatic inflammation and periurethral fibrosis contributes to the development of lower urinary tract dysfunction (LUTD) but current therapeutic efforts do not target these pathologies.
Dr. Popovics has recently identified osteopontin (OPN) as an important cytokine contributing to inflammation in the prostate. OPN is implicated in various fibrotic diseases: OPN delays the resolution of thioacetamide-induced liver fibrosis in mice partly due to its stimulatory action on collagen-I deposition. In wound fibrosis, OPN is induced by fibrocytes and local oligodeoxynucleotide-mediated suppression of OPN reduces scaring and shortens healing time. Dr. Popovics`s recent study found that OPN expression was highly elevated in a rat model of inflammation-induced stromal expansion and prostatic fibrosis and in human prostatic hyperplasia that recognized OPN as a valuable molecular target for prostatic fibrosis.
Dr. Popovics`s current research focuses on identifying which cell type is the source of prostatic OPN during the progression of LUTD, which molecular pathways initiate osteopontin expression and secretion and what genes are activated in response to OPN. Using in vitro 3D cell cultures and animal models of prostatic inflammation and LUTD, she will explore whether genetic and pharmacological manipulation of osteopontin action attenuates inflammatory and fibrotic signals, improves physiological measures of urinary function and whether this can be utilized in the clinical therapy of LUTS. View Dr. Popovics’s CV.
Alejandro Roldán-Alzate, PhD
Dr. Roldán is an Assistant Professor in the Department of Radiology, School of Medicine and Public Health, and Mechanical Engineering, College of Engineering. His mentors are Will Ricke and Wade Bushman. Dr. Roldán has particular expertise in measurement of flow and determination of fluid dynamics by non-invasive imaging, particularly magnetic resonance imaging (MRI). He research will rely on application of this expertise in conjunction with developing technology in MRI to better characterize the size, conformation, and mechanical properties of the prostate, as well as the relationship of these characteristics to urine flow.
Imaging of the prostate to assess the size, conformation, and consistency of the prostate in men with benign prostatic hyperplasia (BPH) remains confusing. Studies seeking to correlate prostate size determined by non-invasive imaging with lower urinary tract symptoms have produced conflicting, inconsistent results. A major reason for this is that very little attention has been paid to the capacity of imaging – particularly magnetic resonance imaging or MRI – to assess the mechanical properties of the prostate. Using mouse models and patients with BPH, Dr. Roldán will test the following hypothesis: benign disease of the prostate results in decreased elasticity and compliance of the prostate and urethra that is accompanied by increased severity of lower urinary tract disease. MRI has been used extensively to characterize size and mechanical properties of the liver. The accuracy of MRI for this purpose has been confirmed by biopsy, surgery, and autopsy findings. Technology increasing the versatility and accuracy of MRI for assessing mechanical properties of solid organs is rapidly developing, but use of this technology to assess benign prostatic disease lags behind. The long term goal of this research is to use MRI to provide clinicians with more specific, accurate data regarding structural properties of the prostate. These data will guide choices of therapy and improve overall outcome of treatment of BPH. View Dr. Roldán-Alzate’s CV