ANN ARBOR, Mich.—University of Michigan researchers have been awarded 13 federal stimulus-fund grants to date, totaling $6.8 million, for research projects involving both adult and embryonic stem cells.
The research funds were included in the $787 billion federal economic stimulus package approved in February, known as the American Recovery and Reinvestment Act. The stem cell research grants are among more than 260 stimulus awards U-M scientists have received so far from the National Institutes of Health.
In addition to using adult and embryonic stem cells, some of the U-M researchers will use induced pluripotent stem cells, or iPS cells. These versatile cells are adult cells that have been reprogrammed to behave like embryonic stem cells.
Sean Morrison, director of the U-M Center for Stem Cell Biology, was awarded a $744,000 stimulus grant from NIH to examine the potential of using human embryonic stem cells to develop a treatment for Hirschsprung disease, a birth defect in which the nervous system that regulates intestinal function does not develop properly.
"The fact that we were among a small number of groups to get Recovery Act funds for human embryonic stem cell research demonstrates that the University of Michigan can compete with any institution in the area of embryonic stem cell research, once we're given the opportunity to do so," Morrison said.
In November 2008, Michigan voters approved a constitutional amendment that relaxed restrictions on embryonic stem cell research in the state. Though Morrison's Hirschsprung study would have been permitted prior to the passage of Proposal 2, the highly restrictive state laws had discouraged many stem cell researchers from pursuing embryonic stem cell research in the state, Morrison said.
"Proposal 2 is going to allow us to hire more people who work in the area of embryonic stem cells, and this NIH grant illustrates that the federal government will provide funding to fuel that expansion," Morrison said.
U-M researchers awarded NIH Recovery Act grants for stem-cell projects include:
- Sally Camper, chair of the human genetics department and a professor internal medicine at the Medical School, was awarded a two-year grant of $974,463 for a study of the genes that regulate cell growth and differentiation in the pituitary gland. Camper will take the lessons learned from the genetic study and apply them in the laboratory to improve techniques to obtain hormone-producing cells from mouse embryonic stem cells. Information from the studies could lead to a better understanding of the causes of pituitary diseases, as well as better treatments.
- Dr. Mario Delmar, Dr. Karen Vikstrom and a New York colleague were awarded $500,000 to examine cardiac stem cells involved in the formation of scars in the heart. Scars can eventually cause severe arrhythmias and even sudden death. The animal studies could lead to new ways to manipulate these stem cells in humans to limit scar formation and prevent cardiac rhythm problems. Delmar is the Frank Norman Wilson Professor of Cardiovascular Medicine and a professor of molecular and integrative physiology at the U-M Medical School. Vikstrom is an assistant professor of internal Medicine at the Medical School. The third project leader is Dr. Stephen Taffet at the SUNY Upstate Medical Center.
- Douglas Engel, chair and professor of cell and developmental biology at the Medical School, was awarded $985,672 for a two-year study that involves reprogramming gene regulation in human blood-forming stem cells in an effort to find new treatments for sickle cell disease and beta thalassemia. Both disorders affect hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. Sickle cell disease affects more than 70,000 Americans and millions of people worldwide.
- Donna Martin, associate professor of human genetics and associate professor of pediatrics at the Medical School, was awarded $264,156 for a study that will use cultured mouse inner ear and neural stem cells to understand the mechanisms behind hearing and balance disorders in CHARGE syndrome patients. CHARGE syndrome affects one in 10,000 newborns worldwide. It is characterized by eye defects, blockage of the nasal passages, retarded growth and development, and ear anomalies that include deafness and vestibular disorders.
- Miriam Meisler, professor of human genetics at the Medical School, was awarded $489,818 to use induced pluripotent stem cells from patient skin biopsies to examine the abnormal activity of nerve cells in an inherited form of epilepsy known as severe myoclonic epilepsy of infancy, or Dravet syndrome, in which infants suffer repeated damaging seizures. Meisler's team includes U-M neurologist Dr. Jack Parent and Lori Isom, a professor of pharmacology.
- Yi Sun, a professor of radiation oncology and director of the Division of Radiation and Cancer Biology at the Medical School, was awarded $596,014 for a two-year study that will use mouse embryonic stem cells and human cancer cells to help define the role the SAG gene plays in forming blood vessels that fuel tumor growth. The ultimate goal is to develop a new cancer therapy that inhibits blood-vessel formation by targeting SAG.
- Dentistry professor Russell Taichman was awarded $971,456 for a two-year study that will use reprogrammed adult stem cells to heal and restore face and skull tissues following disease or trauma. The work may also be applicable to restoring bone tissues lost due to osteoporosis. Taichman's team includes Paul Krebsbach and David Kohn, professors of biologic and materials sciences at the School of Dentistry and professors of biomedical engineering at the College of Engineering.
- Dr. Max Wicha, a professor of oncology and director of the U-M Comprehensive Cancer Center, was awarded $300,000 to work with scientists at Cold Spring Harbor Laboratory in New York to help determine mechanisms involved in the differentiation of breast stem cells that may account for the protective effects of early full-term pregnancy against breast cancer. The work could lead to clinical techniques to mimic that protective effect.
- Wicha and Dr. David Smith, professor of internal medicine and medical director of the U-M Cancer Center clinical trials office, were awarded $71,000 to conduct a Phase 1 clinical trial of two inhibitors of cancer stem cells, a joint project with the Karmanos Cancer Institute.
- Liang Xu, assistant professor of radiation oncology at the Medical School, was awarded $614,396 to explore a nanoparticle-based system for targeted delivery of miRNA-based therapeutics to human pancreatic cancer stem cells. MicroRNAs, or miRNAS, are single-stranded RNA molecules that regulate gene expression in a cell. Xu's work could lead to novel, self-assembled miRNA-nanovectors that can deliver the known tumor suppressor miR-34 to pancreatic cancer stem cells, inhibiting their self-renewal and tumor initiation.
Morrison's team will use human embryonic stem cells to derive a more specialized cell type called neural crest stem cells, which form the nerve cells that line the intestines. Neural crest stem cells will be injected into the large intestines of rats with Hirschsprung disease to test whether the transplanted cells can improve intestinal function. Hirschsprung disease is a serious and sometimes life-threatening intestinal disorder that affects one in 5,000 newborns.
Babies with this disease are born without the nerve cells that trigger contractions to push feces through the large intestine and out the rectum. The result is intestinal blockage requiring surgery, sometimes immediately after birth.
Morrison's team will attempt to restore gut function in rats lacking nerve cells in a portion of the large intestine. The idea is that is that the injected neural crest stem cells will take up residence there and produce the missing nerve cells.
"This is a proof-of-concept study, not a final product that is ready for use in human treatment. We're just scratching the surface," said Jack Mosher, an assistant research scientist at the Life Sciences Institute and a co-investigator on Morrison's grant.
"There are already surgical therapies that take out the part of the intestine that doesn't have the full complement of nerve cells. But often, there's a little bit of gut left over, after surgery, that doesn't have the right mix of cells," Mosher said. "I envision this stem cell treatment as a complementary therapy that might be used along with surgery."
In addition to the Recovery Act awards listed above, Yukiko Yamashita, a research assistant professor at the Life Sciences Institute, was awarded $259,984 for a study of the physiological regulation and function of asymmetric stem cell division using germ-line stem cells from fruit flies. And Steven E. Clark, associate professor of molecular, cellular and developmental biology, was awarded $49,814 to study how cellular signaling affects stem-cell fate in the Arabidopsis plant.
As part of Meisler's epilepsy study, Parent will reprogram skin cells from a child with Dravet syndrome to become iPS cells capable of differentiating into neurons and other more specialized cells. Isom will then measure changes in ionic currents and firing patterns in those neurons.
Acquiring a sufficient number of neurons that carry the genetic mutation responsible for Dravet syndrome will allow the team to explore what goes wrong in this rare form of epilepsy, and to gain insights about other forms of epilepsy as well.
Many other mutations in the same gene are linked to other forms of epilepsy. "Epilepsy affects one in 1,000 people," Meisler said. "If you can understand what is going on in a rare form, you often get an approach for treating more common forms."
"This grant will enable us to move beyond molecular diagnosis into the arena of functional diagnosis," Meisler said. "For the first time, we will have access to the very cells that are misfiring during seizures, the excitatory neurons that carry the patient mutation, as well as the entire genetic background of the patient that is permissive for the abnormal firing.
"Down the road, we hope to use these cultured neurons to test compounds for their ability to reverse the malfunction associated with each type of patient mutation."