Kanchan Chitaley, PhD
and Hunter Wessells, MD

>> Kanchan Chitaley bio
>> Hunter Wessells bio

Lab Members:

Lab Members (from left): Karen Engel, Hunter Wessells, Kanchan Chitaley, Ian Luttrell, Don Huynh, Stephen King

Karen Engel-- Research Technician
Don Huynh-- Research Scientist
Stephen King-- Urology Resident
Ian Luttrell-- Research Scientist

 

Diabetes-associated Erectile Dysfunction:
Vasculogenic Mechanisms

• Research Interests |
• Disease Background |
• Active Clinical Research


• Other Research
|
• Funding

Research Interests Overall Goals:

Through basic science, epidemiological and clinical research, we aim to elucidate the mechanism(s) of penile vascular disease and the resultant erectile dysfunction (ED) associated with diabetes, as well as identify potential new therapeutic avenues to restore erectile function. Our "bench to bedside" approach includes the use of a wide range of molecular, physiologic and epidemiological tools, as well as focused, local clinical studies.

Disease Background:

ED is a complex, multi-factorial disease that is associated with factors ranging from psychosocial (anxiety and depression) to nerve injury (prostatectomy and trauma-induced) to vascular pathologies (hypertension, atherosclerosis). Diabetes uniquely impacts all components of the erectile response, and of all other medical conditions, imparts the greatest risk of ED. The onset of ED is up to 10-15 years earlier in patients with diabetes than in the general population, and current pharmacological therapies are less effective in this patient population. Thus, interventions to improve erectile function in men with diabetes will be important not only to increase quality of life but also to reduce the utilization of health care resources in this rapidly growing subset of the American population.

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Active Basic Science Projects:

1. Microarray Analysis of Altered Gene Transcription in Diabetes-associated Erectile Dysfunction
   We and others have demonstrated that rats made diabetic through drug-induced ablation of pancreatic islet cells have significantly decreased erectile function, as assessed by the in vivo measurement of intracavernosal pressure. Recently, we conducted microarray analysis on isolated penile tissue from non-diabetic control and diabetic rats. We identified expression changes in ~500 genes, including those involved in lipid metabolism, the response to oxidative stress, extracellular matrix factors, and regulators of smooth muscle phenotype. We are currently evaluating the role of some of these genes as potential biomarkers or drug targets for diabetic-ED. The function of one such molecule, ceruloplasmin, in penile physiology and pathophysiolgy is the focus of a current on-going study in the lab.
2. Ceruloplasmin and Diabetic Vascular Endothelial Dysfunction
   Through microarray analysis, we found that ceruloplasmin (Cp), the predominant carrier of copper in the plasma, is up-regulated approximately 3-fold in the penile tissue from diabetic vs non-diabetic rats. Preliminary evidence suggests that the expression of Cp is similarly increased in the penile tissue in diabetic humans as well. Cp is reported to decrease the bioavailability of the potent vasodilator, nitric oxide, through various mechanisms. We are currently using the Cp-deficient (Cp-/-) mouse to determine the effect of the absence of Cp on penile vasodilation and erectile function. In addition, we are performing studies to examine whether the loss of Cp in these mice protects them from the development of erectile dysfunction following diabetic challenge.
3. Adiponectin and Type II Diabetes-Associated Erectile Dysfunction
   Adiponectin, an adipose-produced cytokine, is important for insulin sensitization, and is decreased in type II diabetic patients. Recent studies demonstrate that adiponectin has a vasoprotective role, primarily through direct endothelial and smooth muscle cell signaling. The general hypothesis of this study is that decreased adiponectin in type II diabetes contributes to poor penile vascular function and ED through the loss of nitric oxide-mediated function and vascular cell homeostasis.

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Active Clinical Research:

1. Urological Complications of Diabetes – URO-EDIC
   Type 1 diabetes has long been known to be associated with ED, but the role of glucose control and other complications such as nerve damage and microvascular disease remains unclear in human subjects. Through a unique collaboration with experts in diabetes research funded by the NIH, we are studying risk factors and the role of better glucose control on the development of ED. This ancillary study is part of EDIC, the Epidemiology of Diabetes Intervention and Complications Study. Men in EDIC have been followed for close to 17 years to determine the effect of intensive glucose control on complications of diabetes. URO-EDIC allows us to determine the risk and protective factors involved in the genesis of diabetes associated ED.
2. Vacuum Erection Device for the Improvement of Penile Homeostasis in Patients with ED
   During penile erection following sexual arousal or nocturnal tumescence, distension or stretching of the penis occurs. The objective of this study is to investigate the response of penile erectile tissue to the stretch forces normally occurring during penile erection but absent in men with vasculogenic ED associated with risk factors such as diabetes. We hypothesize that this repeated distention is important for the maintenance of penile cellular health and function. Men with ED who have agreed to treatment with penile implant surgery will be recruited to undergo penile needle biopsy before and at the end of a 1-month use of a vacuum erection devise to induce penile blood flow and stretch. Biopsy samples will be used for the measurement of changes in gene expression and study of vascular function. Results from this pilot study may ultimately lead to a larger intervention studies and have a broad clinical impact on the treatment of men with ED that are not responsive to current pharmacologic therapies.

Active Clinical Trials

Prospective, Randomized, Controlled, Multicenter Trail of the Memokath 044TW Thermo-Expandable Stent for Maintaining Urethral Patency in Patients after Dilation of Internal Urethrotomy of Recurrent Stricture of the Bulbar Urethra

PI: Hunter Wessells, MD
Type: MVU20020001U, Engineers and Doctors, Inc. 1/1/05-12/30/07

The purpose of the study is to determine whether a novel stent is more effective than control in preventing stricture recurrence after internal urethrotomy

Detection of Bladder Cancer by Microsatellite Analysis of Urinary Sediment: Multi-Institutional Study

PI: Hunter Wessells, MD
Type: MSA STUDY, Johns Hopkins University 9/1/06-8/31/07

The purpose of the study is to determine whether MSA can detect incident or recurrent superficial bladder cancer.

>> See other clinical trials.

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Other research

1. Melanocortin Signaling in CNS Control and Regulation of Penile Erection
   Melanocortins are required for physiological sex behaviors and represent an important therapeutic target for the treatment of sexual dysfunction. One melanocortin, Melanotan II, is a novel peptide that was invented by our collaborator, V.J. Hruby. Pilot human studies testing the effects of Melanotan II on sexual function indicate Melanotan treatment to enhance sexual desire and induce erection. We found that Melanotan II works in both the brain and spinal chord to stimulate erectile activity. Currently, we are working to identify the specific melanocortin receptor(s) involved in the central nervous system-mediated pro-erectile effects of Melanotan II.

Current and Past Funding:

• Gene Therapy for Diabetic Penile Endothelial Dysfunction
  RO1 NIH/NIDDK- Wessells (PI) 10/1/00-5/31/06
• Neural Melanocortin Signaling and Erectile Function
  R21 NIH/NIDDK- Wessells (PI) 2/1/04-1/30/06
• Immortalized Human Cavernosal Endothelial Cells
  R21 NIH/NIDDK- Wessells (PI) 9/1/04-8/31/06
• Erectile Dysfunction in Type II Diabetes: Role of Adiponectin
  R21 NIH/NIDDK- Chitaley (PI) 1/06-12/07

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