•Molecular Therapeutics and Drug Discovery •Transplant Science
Our Translational Research Programs combine biology and technology to understand the basis of human disease. How do the muscle cells of the failing heart differ from those of a healthy one? If we pinpoint these differences, can our chemists create a drug or our molecular biologists introduce a gene to correct the problem? Can our stem cell scientists and experimental surgeons replace damaged cells with healthy cells to restore function? In translational research, LHI scientists get one step closer to discovering treatments and cures.
Molecular Therapeutics
and Drug Discovery* (Lung
Injury center, sickle disease/circulating endothelial cells)
David Ingbar
Our research program seeks to understand fundamental mechanisms of cardiovascular
and respiratory diseases, and to utilize this information to develop new therapeutics.
For example, in our Lung Injury Specialized Center of Research, we are learning
how the basic protein synthesis machinery regulates the life and death of a
cell. An over active apparatus selectively suppresses the death of cells with
deregulated growth such as cancer cells or cells forming scar tissue in the
heart or lung, whereas inhibition of the apparatus activates death in these
unwanted cells without harming normal cells. We are now poised to therapeutically
target the protein synthesis apparatus with small organic molecules. In collaboration
with faculty in the College of Pharmacy, Medical School faculty are developing
new high throughput techniques to synthesize and test novel protein synthesis
repressors as potential antiscarring and anticancer agents; and novel protein
synthesis activators as potential protectors of cardiac myocytes and lung epithelium
for use in critically ill patients suffering from heart attack or lung injury.
Other molecular targets being studied include ion channels and transport proteins
for drying out the lung - a major therapeutic goal in premature babies, and
patients with lung injury, pneumonia and heart failure. Our goal is to bridge
the gap between basic biology and testing of this new therapeutics for heart,
vascular and lung disease.
Transplant science* (xenotransplants, chronic rejection)
Agustine Dalmasso, Marshall Hertz, Leslie Miller
The clinical heart and lung transplant programs at the University of Minnesota
have achieved positions of national and international prominence: Our first
heart transplant was performed in 1978 and over 425 pediatric and adult transplants
have been performed since that time. Our first lung transplant was performed
in 1986 and a total of over 400 lung transplants have been performed, including
5 living donor lobar lung transplants. The thoracic organ transplant programs
have strong linkages to multiple L.H.I. clinical programs including heart failure,
mechanical circulatory assist device development, progressive lung diseases
(COPD, Pulmonary Fibrosis), pulmonary vascular disorders, congenital heart
disease, and the developing field of mechanical lung assistance devices. One
major focus for research in lung transplantation has been chronic rejection,
which accounts for the majority for late lung graft loss. We recently were
awarded a NIH funded program project grant entitled "Pathogenesis and
Therapy of Chronic Lung Rejection." This funded research includes projects
using animal models and human biological samples to improve our ability to
understand, diagnose, and treat chronic rejection after lung transplantation.
A second major focus addresses the use of organs from another species for transplantation into humans, termed xenotransplantation. There are too few organs available for transplantation, and xenotransplantation is one logical solution. The focus of the program is a process called accommodation, in which exposure of a non-human organ to certain substances from a potential human recipient alters the organ so that it can survive in the recipient. Since the pig is considered to be the preferred animal species to be used as donors, studies are being conducted to define the interactions between pig cells and human blood after the cells have been exposed to the substances that induce accommodation.. Our studies also address whether such modifications can be induced in pig arteries so that when the arteries are exposed to human blood, they are protected from injury. Ultimately, this approach can succeed if, together with immunosuppressive treatment of the recipient, a modified pig artery or heart is protected from rejection when transplanted into a human.
* = NIH Center, program, or core laboratory
** = NIH MERIT award recipient