Luteinizing Hormone Receptor Activation Induces Migration and Adhesion in Neoplastic Canine Lymphocytes

Luteinizing hormone (LH) is secreted from the brain (pituitary) in sexually intact dogs to stimulate synthesis of estrogen and testosterone in females and males, respectively. However, LH is secreted at concentrations up to 20 times higher following gonad removal with spaying or castration because hormonal negative feedback is lost. Although LH is considered to be a reproductive hormone, there are dozens of non-reproductive tissues in dogs that contain receptors for LH including immune system cells, specifically lymphocytes.

Lymphoma is a common malignant cancer of dogs involving lymphocytes, and spayed/castrated dogs are reportedly 3-4 times more likely to develop lymphoma. Conventional chemotherapy results in remission in approximately 60-90% of cases with a median survival time of 6-12 months. Preliminary work has identified LH receptors in canine lymphoma tissue and demonstrated LH- receptor-induced proliferation of neoplastic lymphocytes in vitro.

This study aims to determine if LH receptor activation induces adhesion and migration of neoplastic lymphocytes in vitro. Characterizing the role of LH receptor in neoplastic lymphocyte proliferation may help guide future lymphoma treatment options.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02751-A

RESEARCHERS

Michelle Kutzler, DVM, PhD; Oregon State University
Amount: $3,000

Identifying Early Stage Ultra-rare Mutations as Predictive Biomarkers of Lymphoma in High-risk versus Low-risk Breeds Within the Dog Aging Project

The most common type of cancer in dogs is lymphoma, with ~80,000 cases diagnosed annually in the United States. Breeds vary in their risk of lymphoma, but it is unclear why there is variation despite considerable effort to identify the genetics of cancer risk and progression in dogs. Cancer typically arises from the accumulation of non-inherited (i.e. somatic) mutations. However, variation among breeds in cancer risk could be due to breed-specific variation in the types of mutations, the rate of accumulation of mutations, or the downstream effects of mutations in healthy dogs.

This study will use novel sequencing technology to test the hypothesis that breed-specific lymphoma risk is due to variation in the frequency and type of rare precancerous mutations. Normally, measuring these low-frequency mutations has been beyond the range of standard sequencing technology, which is limited to detecting mutations present in >1% of cells. The new technology applied here represents a >10,000-fold improvement in accuracy, enabling the investigators to accurately detect a precancerous mutation present at a single site at a frequency of just one out of every 10 million DNA base pairs. By determining if mutation frequency in blood of healthy high-risk and low-risk dogs can predict lymphoma risk, this work could lead to the development of novel tests for the early diagnosis and prognosis of canine lymphoma.

This work has the potential to shed light on the mechanisms that underlie breed-specific variation in lymphoma risk, and in the long term, could lead to the development of novel tests for the early diagnosis and prognosis of canine lymphoma.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2772

RESEARCHERS

Daniel Promislow, PhD; University of Washington
Amount: $10,000

Reprogramming the Tumor Immune Niche in Canine Hemangiosarcoma

Hemangiosarcoma (HSA) is a common, devastating disease of dogs. The malignant tumor is seen frequently in older Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Labrador Retrievers, and Schnauzers, but it can occur in any dog of any breed at any age. Survival times of dogs with the tumor are short, even with surgical removal and standard of care treatment. Inflammation within the tumor tissue is common in canine HSA, and the immune response may contribute to tumor heterogeneity and prognosis for the dog. Yet, the immunological features in the context of the HSA niche are virtually unknown. The investigators have found that HSA cells have a strong capacity to promote proliferation and differentiation of hematopoietic stem and progenitor cells, with increased inflammatory cytokines, suggesting a niche regulatory function of HSA cells.

This study will focus on understanding the functional relationships between HSA cells and immune cells that contribute to the tumor niche to identify molecular mechanisms that regulate critical signaling pathways in canine HSA. This approach will improve our understanding of the tumor immunity and heterogeneity, as well as aid in patient selection for novel immunotherapies.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2759

RESEARCHERS

Jong Hyuk Kim, DVM, PhD; University of Minnesota
Amount: $5,000

Optical Coherence Tomography for Margin Evaluation of Canine Skin and Subcutaneous Neoplasms

Skin cancer is common in older dogs and often requires surgery to treat. For these tumors, the best chance of cure is offered if the surgeon can fully remove both visible and microscopic traces of the tumor. Currently surgeons must rely on pathologist’s assessment of tissues after surgery and the success of the procedure will not be known until several days later. This result is important as residual cancer may need further surgery or other treatments like radiation therapy. Additional treatments such as these can result in further risk and discomfort for dogs as well as be an emotional and financial cost for owners. Optical coherence tomography is an emerging diagnostic imaging tool that uses light waves to generate real-time, high-resolution images of tissue at a microscopic level. These images can be used to evaluate for residual disease at the time of surgery giving immediate feedback to the surgeon.

This study will focus on validating this technology for the imaging of surgical margins of canine skin and subcutaneous tumors. If successful, this technology could be used to assess for residual cancer intra-operatively to benefit patients by guiding accurate treatment recommendations.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2758

RESEARCHERS

Laura Selmic, BVetMed, MPH; Ohio State University Research Foundation
Amount: $5,000

Bladder Carcinogen Exposures in Pet Dogs

Bladder cancer is an aggressive cancer that affects ~ 20,000 dogs per year, and often leads to euthanasia. Certain breeds have a higher incidence of bladder cancer but genetic studies even in the highest risk breeds have been inconclusive and still indicate influence from environmental exposures. The investigators propose that specific household environmental chemical exposures contribute to the risk of bladder cancer in dogs.

In this study, they will measure urinary concentrations of five different chemicals that are known or suspected to be bladder carcinogens, in dogs with bladder cancer compared to unaffected dogs. The investigators will determine whether the presence of certain chemicals is associated with household exposures, based on owner questionnaires and household proximity to industrial sites. Finally, they will determine whether urinary chemical concentrations are linked to early DNA damage in the urinary cells of healthy dogs that do not have bladder cancer. The overall goal of this study is to provide veterinarians and dog owners with evidence-based bladder cancer prevention strategies.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2780

RESEARCHERS

Lauren Trepanier, DVM, PhD; University of Wisconsin, Madison
Amount: $15,000

Transcriptional Profiling of Canine Soft Tissue Sarcoma

Soft tissue sarcomas account for 10-15% of all skin and subcutaneous cancers in dogs. Traditionally, biopsy and subsequent histology have been the primary means of diagnosing these cancers. The histology is assigned to one of three grades ranging from low (grade I), intermediate (grade II), and high (grade III). Histologic grade is currently the key criterion for guiding treatment and determining patient outcome. However, in human medicine and pathology, soft tissue sarcomas are diagnosed with a hybrid approach that involves both histologic features and genetic analysis of the tumor sample. This genetic analysis guides further treatment, aids in developing accurate follow-up information, and has been shown to have a positive effect on patient outcome and survival.

Despite how common soft tissue sarcomas are in the dog, current veterinary care still relies solely on the histologic grade, which is subjective at best, and does not incorporate genetic data into the diagnostic plan. This study will perform transcriptome analysis on 300 canine soft tissue sarcomas in order to establish the transcriptome profile of canine soft tissue sarcoma and correlate this transcriptome to patient follow-up. This will allow for the formation of a hybrid diagnostic approach that will provide more accurate information to inform the prognosis for dogs afflicted with soft tissue sarcoma.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2783

RESEARCHERS

Andrew Miller, DVM; Cornell University
Amount: $10,000

Diagnostic Accuracy of Point of Care Analysis of Canine Urine and Plasma in Marijuana Toxicosis

Given the increase in availability of marijuana in the United States, a higher number of presumed marijuana exposures have been reported in veterinary emergency clinics. Since the clinical signs of marijuana ingestion are non-specific and may be observed in several disorders, an accurate canine bedside diagnostic test may alleviate the need for expensive and invasive diagnostic procedures in canine patients.

To date, no studies have evaluated the accuracy of urine drug screening tests using non-invasive urine or blood samples in dogs. The purpose of this study is to determine the best method to diagnose marijuana toxicity in dogs in a point of care emergency setting.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02692-A

RESEARCHERS

Joel Weltman, DVM; Caspary Research Institute of the Animal Medical Center
Amount: $3,000

Scientific and Clinical Assessment of Fecal Microbiota Transplant in Obese Dogs: SLIM Study

Obesity is a growing epidemic in companion animals. Obesity results from a prolonged positive energy balance leading to excessive fat accumulation, which promotes dysregulation of metabolic, hormonal, and inflammatory responses. Ultimately these changes lead to physical impairment, comorbidities, and reduced quality of life. Evidence is mounting that the intestinal microbiota (collection of microorganisms that live in the intestines) contributes to obesity, and rational manipulation of this ecosystem may confer a health benefit.

This study will provide a comprehensive scientific and clinical assessment of the efficacy of fecal microbiota transplantation (FMT) as an adjunctive therapy for canine obesity management. The investigators hypothesize that FMT (the transfer of feces from a healthy, lean donor dog into an obese dog) will amplify weight loss in obese dogs compared to the use of standard dietary obesity management. A randomized, placebo controlled clinical trial in client-owned obese dogs consisting of three groups: diet alone, diet + FMT, diet + placebo will provide data on weight loss and characterize the intestinal microbiota and metabolic function. Success of this study will benefit obese dogs by providing a microbial intervention to augment current strategies for canine obesity management aimed at promoting weight loss, normalizing metabolic status, and improving quality of life.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2723

RESEARCHERS

Jenessa Winston, DVM, PhD; The Ohio State University
Amount: $5,000

Evaluation of Serum Zonulin as a Non-invasive Biomarker and Therapeutic Target in Dogs with Chronic Canine Enteropathy

Canine chronic enteropathy (CE) is the most common cause of gastrointestinal (GI) disease in dogs. The exact mechanisms causing CE are unknown, however, disruption of the inner lining of the GI tract is believed to play a significant role resulting in a “leaky” GI tract, leading to absorption of GI contents and overstimulation of the immune system.

Unfortunately, treatment for CE currently requires life-long management such as food elimination diets which can be expensive and labor intensive for owners and/or require the use of medications which carry the risk for significant systemic side effects. Diagnosis and monitoring for disease relapse rely upon owner reported clinical signs and invasive diagnostic testing such as endoscopic intestinal biopsies. Thus, non-invasive diagnostics as well as specific treatments are needed. Zonulin, a protein found in animals and humans, plays an integral role in maintenance of intestinal barrier.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2684

RESEARCHERS

Jamie Kopper, DVM, PhD; Iowa State University
Amount: $3,000

Pattern of Thyroid Function Tests during Recovery from Acute Nonthyroidal Illness

Hypothyroidism is the most common endocrine disease in dogs. A diagnosis of hypothyroidism relies on finding both appropriate clinical signs and low thyroid hormone levels. Unfortunately, other illnesses can suppress thyroid hormone levels and result in a misdiagnosis. This phenomenon of low thyroid hormone levels caused by a disease not involving the thyroid gland is known as nonthyroidal illness or euthyroid sick syndrome. It is important to distinguish between nonthyroidal illness and hypothyroidism as the treatment for each is different. Historically, the recommendation for a dog with nonthyroidal illness has been to resolve the underlying disease, followed by a recheck of thyroid hormone levels thereafter. However, the duration of time after resolution of the nonthyroidal illness necessary to perform accurate thyroid hormone level testing is unknown.

This study will provide information about thyroid hormone levels during the course of nonthyroidal illness, and also establish the approximate duration of time for recovery of thyroid hormone levels to normal following illness resolution. These results will correlate clinically with more concrete recommendations for thyroid hormone level testing following resolution of nonthyroidal illness.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2686

RESEARCHERS

Timothy Bolton,DVM ; Virginia-Maryland Regional College of Veterinary Medicine
Amount: $3,000