Knuppe Molecular Urology Laboratory
H. James and Barbara J. Knuppe Molecular Urology Laboratory
- Tom Lue- Medical Director
- Ching-Shwun Lin- Professor - molecular biology director
- Guiting Lin, Associate Professor- molecular biology co-director
533 Parnassus, Room U212
Lia Banie 415.476.3801
Funding sources: NIDDK and H. James and Barbara J. Knuppe, NIDDK
Stem Cell Research
Current research is focused on basic and clinical studies of adipose-derived stem cells (ADSC). Basic studies include investigations of the molecular mechanisms that mediate ADSC differentiation into neurons, Schwann cells, smooth muscle cells, and endothelial cells. The lab also studies molecular markers that can be used to identify and/or to facilitate the isolation of ADSC. These markers, both positive and negative, include CD31, CD34, and Stro-1. Stro-1 is of particular interest because this cell surface protein is widely considered to be the most reliable marker for mesenchymal stem cells (MSC), which include ADSC. Contrary to most of the published data concerning Stro-1, ADSC are vascular stem cells (VSC), and that other types of MSC may also be VSC. The lab also conducts preclinical studies of the role of ADSC in erectile dysfunction (ED), urinary incontinence (UI), and diabetes. This research has shown that ADSC was able to restore erectile function in animal models of both neurogenic and vasculogenic ED. Other research has shown that ADSC was able to greatly improve continence in animal modes of both stress and urge types of UI. Knuppe Lab research has also led to the establishment of ADSC cell lines that synthesize and secrete large quantities of insulin and are capable of reducing blood glucose levels in type I diabetic rats. Several ongoing clinical trials are based on results from the lab’s animal studies.
Molecular Mechanism of Impotence
Tom F. Lue, MD has developed several animal model for studying ED from different diseases. The lab is using these models to identify genes that are involved in the development of impotence. The preliminary data showed that a novel variant of the neurological form of nitric oxide synthase (nNOS) might be differentially expressed in normal and impotent animals. Other genes, such as androgen receptor and phosphodiesterases, are also being investigated currently.
Molecular Mechanism of Female Stress Urinary Incontinence
Urinary incontinence is a major social and economic problem. In particular, female incontinence is estimated to afflict approximately 20 million American women. By using an animal model developed in our lab, we are currently investigating genes that may be involved in the atrophy of muscles and nerves. We are also comparing genes of several growth factors, neurological receptors, and steroid hormone receptors in normal and diseased urinary bladders and urethras.
Molecular Mechanism of Peyronie's Disease
Men with this disease have a bent penis during erection. Lue's team has discovered that transforming growth factor (TGF-b) is produced in excess in the diseased tissues. Ching-Shwun Lin, PhD is now developing a cell culture model to further study at the molecular level both the cause and the consequence of excessive production of TGF-b.
Molecular Mechanism of PDE5A Gene Regulation
The Knuppe lab has cloned the promoter of the PDE5A gene, whose product is the target of PDE5 inhibitors (i.e., Viagra, Cialis, and Levitra). Dr. Lin also discovered that the PDE5A gene encodes 3 isoforms that differ in the amino terminal. The researchers systematically mapped where these isoforms are synthesized in the body. One of the most surprising findings is that, despite being smooth muscle specific, PDE5 is abundantly expressed in the striated muscles that control urination (the urethral sphincter and the levator ani muscles).
Molecular Marker of Prostate and Bladder Cancer
Ching-Shwun Lin, PhD has identified and cloned a gene called L-plastin, which is abnormally synthesized in a variety of cancers, including prostate and bladder cancers. The L-plastin gene is not only a marker, but also a potential target for gene therapy for these cancers. He has identified several genetic elements in the L-plastin gene promoter as potential targets for hormonal actions. Specifically, he has shown that the L-plastin gene can be activated by estrogen, progesterone, and testosterone.
Roles of Integrins in Cancer and Urological Diseases
Integrins are transmembrane receptors for extracellular matrix proteins. They play important roles in both normal cell functions and disease development. The lab has identified a6 integrin as an important molecule in the development of fibrosarcomas and breast cancer. Abnormal expression of integrins has also been reported in a variety of urological diseases. Ching-Shwun Lin, PhD will use his expertise in integrin research to study urological cancers and degenerative urinary diseases (impotence and incontinence).