A little-known aspect of cells is that they sometimes respond to getting pushed around. That is, the mechanical pressure of cells with different physical stiffness or squishiness coming into contact with each other is one way that they signal to each other and induce biological changes, such as tumors invading other tissues and metastasizing, and stem cells differentiating and developing into mature cell types. But most of this knowledge about cells’ mechanical signaling behavior comes from in vitro studies, not from studies of living tissue in organisms.
Christoph Seiler, PhD, received a Foerderer Fund for Excellence award at The Children’s Hospital of Philadelphia in 2015 to study this mechanism.
German-born Dr. Seiler pointed out that “Foerderer,” in German, means supporter or sponsor. Its name is therefore apt, because the internal award program spurs research projects that need a bit of support to generate pilot data that can later help those projects stand out in the competitive awarding of external funds. (The award name itself honors a philanthropist who helped start the program, and its German translation is mere coincidence.)
Dr. Seiler’s main role at CHOP as director of the zebrafish core is to support investigators who want to use this model organism for developmental biology research. With the Foerderer grant, he is branching out into his own novel project that draws on his background in both developmental biology and intestinal disease.
“It’s hard to figure out the mechanical properties of a whole tissue, especially at a very small scale,” Dr. Seiler said. “That’s why I thought this might be interesting in a zebrafish, which is transparent as an embryo. I can modify the mechanical properties of intestinal cells and see if that affects differentiation.”
His findings could provide clues to disease progression mechanisms in cancer and inflammatory bowel diseases.
CHOP’s Foerderer Fund for Excellence awards are designed to allow ongoing research to move into new and productive areas, or allow investigators to apply new research techniques toward novel investigations. With the 2016 solicitation for applications opening soon, we are taking a look back at the projects funded in 2015. These 12 research projects — Dr. Seiler’s and 11 others detailed below — span a variety of topics in basic, translational, and clinical research.
Erik DeBoer, PhD, a research fellow in Psychiatry, is taking an up-close look at the potential differences between neurons in people with schizophrenia (in the specific genetic form caused by 22q11.2 chromosome deletion syndrome) and in unaffected individuals. Dr. DeBoer’s study uses newly developed optogenetic technologies to learn more about the functional differences in schizophrenia.
Joshua Jackson, PhD, a scientist in Child Development, is exploring the mechanisms by which astrocytes, a type of cell in the brain, control the change of blood flow patterns to deliver increased oxygen and energy to active brain tissue. This process, termed neurovascular coupling, is inhibited in many disorders including brain trauma or stroke. He is investigating the role of mitochondria, the organelle that serves as the cell’s power plant, in the neurovascular response.
Mitochondrial and Epigenomic Medicine
Piotr Kopinski, an MD/PhD student at Penn and a Howard Hughes Medical Institute International Student Research Fellow at CHOP’s Center for Mitochondrial and Epigenomic Medicine, aims to define changes in the cell that occur due to dysfunction of mitochondria. His work may improve understanding of the possible mechanisms causing multiple common diseases that affect children and adults, including diabetes, autism, Parkinson’s disease, sudden infant death syndrome, and cancer.
Changhong Li, MD, PhD, a research assistant professor of Pediatrics in the Division of Endocrinology, is investigating the role of the protein CFTR in diabetes that occurs as a common but devastating complication of cystic fibrosis. Dr. Li hypothesizes that the protein plays a “fine-tuning” role regulating insulin secretion and balancing intracellular calcium levels in pancreatic beta cells, and aims to further unravel the molecular mechanism of beta-cell dysfunction in cystic fibrosis related diabetes.
Hong Lin, PhD, a research associate in Neurology, is investigating whether drugs can restore certain molecular functions that are damaged in the most common inherited form of the neurodegenerative disorder Friedreich's ataxia. Dr. Lin's work, studying the role of the disease protein in mitochondria and neuronal synapses, aims to provide novel avenues for drug development for this condition, which currently has no cure or effective treatment.
Adriana Mantegazza, PhD, a senior research investigator in Cell Pathology, is studying mechanisms of immune system disruption in the rare autoimmune disease Hermansky-Pudlak syndrome type II (HPS2). Dr. Mantegazza’s study uses an animal model of the HPS2 to better understand how the lack of the protein AP-3 in this disease affects the mechanism of immune system signaling via inflammasomes in dendritic cells, resulting in recurrent infections.
Jason Mills, PhD, an investigator in the Division of Genetics, is using induced pluripotent stem cells to model molecular pathways involved in neurological development in Cornelia de Lange syndrome (CdLS). This rare genetic condition is characterized by numerous physical, intellectual, and behavioral differences. He has already found promising results suggesting ways intellectual disability may originate, including differences in the pace of neuronal development in CdLS cells compared to control cells.
Dimitri Monos, PhD, director of the Immunogenetics Laboratory and a professor of Pathology at Penn, aims to find out what the molecule miR-6891 does in immune cells. This microRNA molecule is encoded by an intronic sequence within the HLA–B gene, one of the Human Leukocyte Antigen (HLA) genes, whose products play a major role in antigen specific immune responses in autoimmune diseases and transplantation. This molecule’s function is not currently known. Their findings eventually set the stage for investigating the role of MHC-encoded miRs in human diseases.
Alejandro Monteys, PhD, a scientist in Hematology, aims to develop a genome editing approach to terminate expression of the mutant form of the huntingtin gene, which causes the inherited neurodegenerative disorder Huntington disease. By turning off this mutated gene’s expression, he hopes to stop the development of the disease.
Tim Olson, MD, PhD, an attending physician and assistant professor of Pediatrics in Oncology/Hematology, aims to study genetic changes in bone marrow cells that arise in response to selective pressure to restore blood cell production in patients with bone marrow failure diseases including acquired aplastic anemia. In children and adults, this devastating disease is caused by immune system attack of the bone marrow, eliminating the normal production of blood cells. Dr. Olson aims to identify genetic changes that commonly arise in surviving cells that may enable immune escape but also may affect response to treatment and lead to the development of myeloid malignancy.
Stephen Zderic, MD, an attending physician in Urology working with Rita Valentino, PhD from Anesthesia and Critical Care, both also professors at Penn Medicine, aims to better define the brain-bladder connection with a long term goal of developing effective treatments for urinary incontinence. The study uses optogenetic methods, and takes advantage of two strains of transgenic mice which drive the expression of the photosensitive molecule rhodopsin in select neural populations. These tagged nerves can then be activated by exposing them to laser light that is delivered precisely by fiber optic probes that are placed in key areas of the brain under stereotactic guidance.
CHOP investigators interested in applying for the 2016 Foerderer Awards should consult the application guidelines on the Research Institute Intranet. The application deadline is April 21, 2016.