Research at the Schnell Lab
We work at the interface between biophysical chemistry, mathematical and computational biology, and pathophysiology. Our primary research interest is to use mathematical, computational and statistical methods to design or select optimal procedures and experiments, and to provide maximum information by analyzing biochemical data. Much of our work focuses on protein aggregation and fibrillation, which is the underlying cause of protein folding diseases, such as diabetes, cystic fibrosis, Alzheimer's, Parkinson's and Huntington's disease and cataract. Protein folding diseases are triggered by the inability of the cells to cope with inherited misfolding-prone proteins, aging, metabolic or environmental stress.
Through a multidisciplinary approach and application of state-of-the-art chemical kinetics, molecular modeling, computational modeling and scientific computing, the Schnell Lab hope to gains critical insights into protein aggregation and build a comprehensive understanding of protein folding diseases. Our work is strictly theoretical, but we maintain a close coupling between experimental work and modeling results with our collaborators at the University of Michigan, across the USA and abroad.
Although our primary research interest is in protein folding diseases, we also investigate other complex physiological systems comprising many interacting components, where modeling and theory may aid in the identification of the key mechanisms underlying the behavior of the system as a whole.
Chemometrics and reproducibility: Protein aggregation as a case study
One of the key objectives of our research is to create suitable standards and appropriate support of standards leading to reproducible results in the biochemical sciences. Reproducibility is central to scientific credibility. Meta-research has repeatedly shown that accurate reporting and sound peer-review do not by themselves guarantee the reproducibility of scientific results. One of the leading causes of poor reproducibility is limited research efforts in quantitative biology and chemometrics. We are developing new ways to assess the reproducibility of quantitative findings in the biochemical sciences by:
As a case study, we use protein aggregation and fibrillation for our research efforts in this area.
Characterization of aggregation reactions and amyloid formation
It is increasingly clear that peptides and proteins are inherently susceptible to aggregation and amyloid formation, and that these processes directly or indirectly underlie pathological events associated with numerous protein folding diseases. Using chemical kinetic theory, we are investigating the principal molecular events in the process of aggregation and the effects of inhibitors of amyloid fibrillogenesis. Determining protein folding reaction mechanisms is of paramount importance to develop drug targets to control protein folding diseases.
Morphogenesis of the intestine
The huge surface area of the intestine is critical for its efficient function in nutrient absorption, but little is known about how intestinal cell differentiation occurs and how intestinal surface area is generated in the fetus.
In collaboration with Drs. Deborah Gumucio and Linda Samuelson, we are investigating the morphological and molecular processes that occur in the early mouse intestine and are required for the establishment of intestinal crypt, absorptive surface and intestinal length. The work could suggest therapeutic strategies for infants diagnosed with short bowel syndrome in utero or perinatally.
GnRH neuron feedback control of ovulation
Precise timing of ovulation is required for reproductive success. Ovulation is triggered when estradiol switches from negative feedback action on the pituitary and hypothalamus to positive feedback, initiating a surge of gonadotropin-releasing hormone secretion that causes a surge of luteinizing hormone release, which triggers ovulation.
Our understanding of the neurobiological mechanisms underlying the switch from negative to positive feedback is incomplete. In collaboration with Dr. Suzanne Moentor, we are investigating how GnRH neurons switch from negative to positive feedback control by integrating multiples changes to thier synaptic inputs and intrinsic properties.
Modulation of aging
Sensory perception can modulate aging and physiology across different organisms. Aging is actively regulated throughout an organism's life, but how this occurs in individuals is largely unknown. To understand how aging is temporally regulated in individuals, we are investigating with Dr. Scott Pletcher, how individuals patterns of aging control group mortality rates. As a case study, we are investigating how the fly lifespan and physiology are modulated by sexual perception and reward.
Identification of key metabolic intermediates of cancer progression
Cancer is characterized by unchecked cellular proliferation, increased local invasion and, ultimately, metastases. Despite the enormous amount of genetic diversity found in tumors, many of the same protein signaling and metabolic pathways are routinely altered in cancer cells. An altered metabolic phenotype, characterized by high rates of glucose uptake and glycolysis, is also associated with cancer progression.
In collaboration with Dr. Sofia Merajver, we are developing multiscale models of cancer progression to discover the key metabolic intermediates that are most likely to modulate cancer progression with limited cytotoxic effects on normal tissue. Our models will greatly improve cancer therapy and lessen complications in cancer patients by seeking metabolic and protein targets in a rational way.
Elucidating the mechanism of insulin biosynthesis
Pancreatic β-cell failure is increasingly recognized as central to the progression of diabetes mellitus. Different causes are implicated in the onset of β-cell stress, dysfunction or dead. Failure in modulating the capacity and quality production of insulin is one of the leading causes of β-cell stress. In the β-cells proinsulin represents up to 50% of the total protein synthesis, and the rate of glucose-stimulated proinsulin translation is approximately 1 million molecules per minute per cell.
In collaboration with Drs. Peter Arvan and Ming Liu, we are investigating the insulin biosynthesis pathways. The results of our work promise to elucidate the mechanism responsible for the pathogenesis of some diabetes mellitus.
Investigating how mRNA expression and protein abundance are coordinated in the cell
The human genome contains at least 80,000 non-redundant non-coding RNA genes, outnumbering protein-coding genes by at least 4-fold, a revolutionary insight that has led some researchers to dub the eukaryotic cell an “RNA machine”. Yet, how exactly these non-coding RNAs guide every cellular function – from the maintenance and processing to the regulated expression of all genetic information and proteins– is still only poorly understood.
In collaboration with Dr. Nils Walter, we are developing a single molecule systems biology pipeline to understand the how the RNA machinery controls protein expression in cell.
The Schnell Lab, University of Michigan Medical School
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