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 optimal procedures and experiments that allows us to quantitatively measure and analyze biological data. Measurements in biology matter to us. Our research is in the science of measurement in biology: biometrology. Accurate and reliable measurements are one of the foundations of high-quality research, leading to rigorous, reproducible and robust scientific results.

 

Much of our work focuses on enzyme catalyzed reactions, and protein aggregation and fibrillation. Aberrant  protein aggregation is the underlying cause of many 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 stress, or environmental stress. Through a multidisciplinary approach and application of state-of-the-art chemical kinetics, mathematical and computational modeling , and scientific computing, the Schnell lab hopes to gain 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 applying biometrology to enzyme kinetics and aberrant protein aggregation, we are also part of collaborative project that investigate 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.

Reproducibility and chemometrics of enzyme catalyzed reactions

One of the key objectives of our research is to create suitable standards and methodologies to measure the rates of enzyme catalyzed reactions.  Reproducibility is central to scientific credibility. Dr. Schnell is a member of the Standards for Reporting Enzymology Data (STREDA) commission. STRENDA was constituted under the auspices of the Beilstein-Institut and its foundation. The STRENDA Commission has developed STRENDA Guidelines to compare, evaluate, interpret and reproduce enzyme assay experiments. However,  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 measurement science in enzyme kinetics.

We are developing new ways to assess the reproducibility of quantitative estimates of kinetics parameters of enzyme catalyzed reactions by:

  • Developing and implementing of mathematical, computational, and statistical methods to identify and characterize reaction mechanisms.
  • Investigating and testing performance design of experiments or standards to quantify, interpret and analyze time course and initial rate data.
  • Developing of new algorithms and software to analyze the results of enzyme assays.

In this area, we collaborate with our colleagues from the STRENDA Commission in this research effort.

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.

In this area, our laboratory collaborates with members of the University of Michigan Protein Folding Initiative, including Dr. Henry L. Paulson, Dr. James Bardwell, Dr. Ursula Jakob, and Dr. Andrew P. Lieberman.

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 their synaptic inputs and intrinsic properties.

Biochemical regulation of endocytosis

Endocytosis is a fundamental cellular process that governs nutrient uptake and intracellular signaling. With these key roles, endocytosis is critical for cellular and organismal homeostasis and is expected to interface with other cellular processes, such as cell migration and cell division. Identification of the mechanisms that modulate how clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE) regulate receptor spatial organization and downstream signaling has both preventive and therapeutic value.  In collaboration with Dr. Allen Liu, we are investigating the mechanism and molecular components regulating CME and CIE. To examine the dynamic of endocytosis, we re using state-of-the-art live cell imaging, computational image analysis, cell biology approaches, spatially-resolved proteomics and phospho-proteomics, and rule-based modeling.

Elucidating the mechanism of diabetes etiology

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 Ling Qi  we are investigating the insulin biosynthesis pathways, and causes of β-cell stress.  We are also collaborating with Dr. Scott Soleimanpour to study the mitochondrial life cycle in the pancreatic β-cells, which helps to maintain proper glucose stimulated insulin release.

 

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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