P53 as a Downstream Mediator of Signaling by Antiproliferative Factor (APF) Jayoung Kim, PhD
Enders Research Laboratories
Boston, MA
This study is investigating the mechanism of action of antiproliferative factor (APF), a protein which has been found to be elevated in the urine of people with IC and which appears to slow down the growth or regeneration of bladder cells. Specifically, this study is looking at the protein P53 and its relationship to APF and cell growth regulation. Findings may help to develop specific biomarkers that could be used to diagnose and treat IC.
Autoantibody Signatures as Biomarkers of Interstitial Cystitis
Brian Liu, PhD
Harvard Medical School
This researcher proposes that the presence of inflammation/autoimmunity in IC may allow for the use of the body’s own immune response as a means of identifying IC biomarkers. This project will test the idea that blood samples from IC patients can be used to create a sensitive and specific biological profile of IC and will investigate the feasibility of autoantibody screening to detect IC.
Relationship Between Lactogenic Hormones and Stress in Interstitial Cystitis
Timothy Ness, MD, PhD
Anesthesiology Research Division
University of Alabama
South Birmingham, AL
Women with the painful bladder disorder, interstitial cystitis, have noticed that their bladder pain sometimes improves during pregnancy and afterwards while breastfeeding. The present research study examined whether breastfeeding and the hormones that are associated with breastfeeding, prolactin and oxytocin, might have effects on bladder pain in a non-human animal model. It was identified that lactating rats have less intense pain-related reactions in response to distension of the bladder. The hormone that appears to produce this effect was identified as oxytocin since it was demonstrated to reduce bladder pain-related responses when administered by itself. It was also demonstrated to reduce anxiety-related behaviors in an animal test model. It also reduced the exacerbation of pain-related responses that is produced by anxiety. This was tested in a model of stress-induced pain hypersensitivity that was developed using the support of this grant. In all of these tests, the other hormone, prolactin, did not appear to reduce bladder pain-related responses. These findings suggest that oxytocin and similar drugs might be useful for the treatment of the pain of interstitial cystitis.
Identification of Agents that Inhibit APF Production or Activity – Potential IC Therapies
Chen-Ou, Zhang, MD
Department of Pathology
University of Maryland School of Medicine
VA Medical Center
Baltimore, MD
The small protein antiproliferative factor (APF) is known to play a role in destruction of bladder lining cells in IC patients, so neutralizing APF might be a valuable treatment for IC. One way to neutralize a protein in the body is to make antibodies to it. The University of Maryland team recently made antibodies in rabbits against APF and found that the antibodies did inhibit some of the effects of APF on bladder lining cells. Now, Dr. Zhang and her colleagues will test these antibodies to see if they normalize other functions of cells from IC patients. They will also determine whether an antibody made against both the protein backbone and sugar components of APF might work better than antibodies against only the protein backbone. In addition, the team hopes to find a way to inhibit production of APF using a technique called RNA interference. Normally, RNA is involved in the production of proteins by “reading” the genes in cells’ DNA to assemble proteins, but short sections of RNA, called short, interfering RNA (siRNA), can silence genes so the proteins they code for won’t be produced. An siRNA that helps block APF production might also be a useful treatment for IC.
Noninvasive Test of Bladder Epithelium in Interstitial Cystitis
Deborah Erickson, MD
Division of Urology
University of Kentucky College of Medicine
Lexington, KY
A method of identifying proteins, called quantitative fluorescence image analysis, will allow Dr. Erickson and her team to look for a way to check markers of IC in patients’ urine and also to see if commonly used IC drugs actually change these markers when the drugs are added to cultures of bladder lining cells. Having a way to test urine for IC markers, of course, would be easier on patients than invasive or painful tests such as cystoscopies, potassium sensitivity testing, and biopsies. Bladder lining cells in IC patients’ urine are known to produce higher levels of E-cadherin or beta catenin and lower levels of alpha catenin and vimentin than cells in healthy patients’ urine. If the team finds differences between the levels of proteins in the urine of IC patients with Hunner’s patches, IC patients without Hunner’s patches, and healthy people, this might be a way to test for IC. The investigators will also use this analytic technique to look for differences in expression of the proteins alpha-catenin, alpha-2-integrin, and vimentin in cultures of bladder lining cells from IC patients and healthy subjects and then find out if applying heparin or pentosan polysulfate (Elmiron) to the patients’ cells can change their protein expression to be more like that of healthy people.
Familial Aggregation of Interstitial Cystitis with Other Functional Autonomic Disorders
Thomas Chelimsky, MD
Associate Professor of Neurology
Director, Autonomic Disorders
Case Western Reserve University
Cleveland, OH
The autonomic nervous system controls the functions of the body’s internal organs, including the bladder. Dr. Chelimsky and his colleagues treat many patients with disorders of that system, including fainting, big drops in blood pressure when you stand up, rapid pulse when you stand up, and various pain disorders, such as irritable bowel syndrome. These physicians noticed that many of their patients or their family members have IC, which fits in with the idea that IC may have a basis in the nervous system. The researchers will use a questionnaire, that includes the O’Leary-Sant Symptom and Problem Index for IC to see if the nonbladder disorders are truly more common in the families of patients with IC and whether patients with the dysautonomic disorders have more family members with IC than similar healthy people. This could tell us whether there is a genetic relationship between IC and these other problems and could lead to uncovering the genes responsible and to treatments that could be helpful for all of these problems. If the problems seem to be inherited from mothers, that may suggest a problem with mitochondria, the energy generators of cells, which are passed on only from the mother.
Candidate Gene Identification in Interstitial Cystitis
Jordan Dimitrakov, MD, PhD
Freeman Lab
Harvard Urological Diseases Research Center
Harvard Medical School
Boston, MA
Dr. Dimitrakov and his team believe that genetic mechanisms underlie most, if not all the symptoms that patients with IC experience. Geneticists know that studying populations with a high prevalence of a genetic condition makes the identification of candidate genes easier, and there is a population like this among the Bulgarian Roma people. The researchers’ preliminary genetics work showed there is a link between DNA markers and IC in this population, which has a high incidence of IC. The investigators will be using state-of-the-art technology and the expertise of Harvard geneticist Louis Kunkel (a Howard Hughes Investigator who identified the gene responsible for Duchenne’s muscular dystrophy) to examine the DNA of Bulgarian IC patients and controls. Those tests involve using probes—short strings of DNA—with a sequence that is complementary to those of the mutated gene. These probes will seek their complements within an individual’s genome. If the mutated sequence is present in the patient’s genome, the probe will find it and bind to it, flagging the mutation. Another type of gene tests involves comparing the sequence of DNA bases in a patient’s gene to a normal version of the gene. Once they have identified the gene or genes in the Bulgarian population, they will use that as a template to find the mutations in the same gene in the US population, which will be the key to tolls for effective diagnosis and treatment of IC, including gene therapy.
Traditional Chinese Medicine and Acupuncture in the Treatment of IC: Relationship of Outcome to Modulation of the Stress Response System
Larissa Rodriguez, MD
Department of Urology
UCLA School of Medicine
Los Angeles, CA
Traditional Chinese Medicine (TCM) emphasizes that emotional well-being and physical health are linked. Dr. Rodríguez proposes that people with IC suffer from imbalances in responses to stress and physical and emotional stimuli, making them more prone to experience pain and urinary symptoms. Therefore, she plans to study the differences in responses to fear and stress in patients with IC and those without it.