Wharton Summer Student Research 2019

Program Details

The Wharton Summer Student Research Program is a paid, 10-week opportunity for rising junior and senior undergraduate students in nutrition to participate in research projects under the direction of faculty members in the Department of Nutrition. 

In 2019, the program will begin on May 28, 2019 and end on August 2, 2019.  Participating students receive a stipend and are expected to devote 40 hours per week to their projects for the full 10 weeks.  Any questions can be addressed to nutrition@case.edu.

Eligibility and Applications

Current sophomore and junior undergraduate students who have declared a major in Nutrition or Nutritional Biochemistry and Metabolism no later than January 2, 2019 and have not previously participated in the Wharton Program are eligible to apply for a Wharton Summer Student Research project.  Interested students may apply via this link.  Applications are due by Monday, February 4, 2019 at 5:00 p.m.

Available Projects for Summer 2019

CoA Synthesis by ß-Alanine

Investigations on the stimulation of coenzyme A (CoA) synthesis by β-alanine

The previous phase of our investigations on the side-effects of β-alanine ingestion revealed that β-alanine stimulates liver and brain CoA synthesis without being itself incorporated into new CoA molecules. Because the stimulation of CoA synthesis is greater than the pool of pantothenate (vitamin B5), it appears that β-alanine causes the release of pantothenate from unknown storage form(s). One goal of this phase of the project is to identify the unrecognized storage forms of pantothenate. This will involve metabolomic assays of (i) rat livers and brain, and (ii) pig muscle processed in order to release pantothenate. The pig muscles will the obtained from pig legs perfused in the Department of Plastic Surgery of the Cleveland Clinic. The perfusion medium will contain various concentrations of β-alanine to stimulate CoA synthesis in muscle. These pig leg perfusions are used to set up techniques for future limb transplants in humans. These experiments will inform on the maintenance of muscle CoA concentrations during the normothermic perfusion of the limb before transplantation. Additional assays will be conducted on the pig muscle samples: concentrations of citric acid cycle intermediates, profile of CoA and carnitine esters, rates of substrate utilization, etc.These assays will be conducted by different mass spectrometric techniques which the student will learn to master over the course of summer 2019. This project represents a transition between two different projects: (i) the metabolic consequences of the ingestion of β-alanine by athletes, and (ii) the preservation of perfused limbs prior to transplantation. The common section between the two projects is alterations of CoA homeostasis induced by a drug (β-alanine) or by reperfusion injury.

Henri Brunengraber, MD, PhD


The Role of Pck1 in the Gut Microbiome

Phosphoenolpyruvate carboxykinase (Pck1) is a metabolic enzyme that is integral to the gluconeogenic and glyceroneogenic pathway.  We investigated the role of Pck1 in macrophages using stable isotopomer mass spectrometry analysis in a novel mouse model with a deletion of Pck1 in myeloid cells (Pck1-MCKO).  We showed that deletion of Pck1 in the myeloid cells increased phosphoenolpyruvate (PEP) concentrations, which alters calcium levels in the ER inducing ER stress.  The consequences of altered metabolism in the macrophage are increased expression of M1 cytokines TNFα, IL-1β and IL-6. Thus, Pck1 expression contributes to the polarization of M1/ M2 macrophage phenotype.  

The goal of the summer research is to determine the consequences of this altered immune cells on the development of alcohol induced liver disease. We have fed mice a diet containing ethanol and found that the mice PCK1-MCKO mice were protected from the deleterious effects of alcohol. They had reduced liver injury as measured by ALT levels. The PCK1-MCKO mice also had reduced lipid uptake in the intestine, which suggests that the gut microbiome has been altered due to the changes in the macrophage phenotypes. The research will focus on the gut microbiome and determine the mechanism of protection from alcohol in the PCK1-MCKO mice.

Colleen Croniger, PhD


Normative Values for Handgrip Strength

Expanding Diversity in Normative Data for Handgrip Strength

Reduced muscle strength and function has been associated with malnutrition. The Academy/ASPEN consensus statement includes diminished functional status measured by handgrip strength as one of the six clinical characteristics that can be obtained to identify malnutrition. Research indicates reduced handgrip strength can show an earlier response to nutritional changes than labs and anthropometrics, however a limitation with the normative values utilized with the Jamar hydraulic hand dynamometer is that these values were obtained from a relatively limited population. The purpose of this study is to establish normal handgrip strength values utilizing the Jamar dynamometer in the healthy population. The current normative values lack diversity so we are adding to the sample in terms of size and racial/ethnic diversity.

Rosa Hand, PhD, RDN, LD, FAND


Diabetic Retinopathy

Targeting Diabetic Retinopathy with Protein Therapeutics 

Diabetic retinopathy is a model of a vascular disease that has a strong para-inflammation component. In transgenic animals ablation of ICAM or CD18 or TNFα or IL-1ß signaling inhibits diabetes-induced degeneration or permeability of retinal capillaries suggesting that this the major route through which diabetic retinopathy (DR) develops. Furthermore, this is not a complication that is relegated to poorly managed Type I diabetes as even well managed cases of diabetes have a significant chance of developing DR. 

A family of proteins produced by Ascaris and other hookworm sp. known as Neutrophil inhibitory factor (NIF) has been shown to assist in their efficient evading of the human immune system. This protein has been shown to bind to the I-domain of CD11b, and the NIF-I domain interaction surface mapped to a specific surface upon the I domain. In transgenic mice, the expression of NIF inhibits the progression of DR. Previously, we were awarded a one year grant from the JDRF to biochemically and biophysically characterize the interaction between NIF and CD11b. These studies enabled us to validate this interaction as a target for treatment of DR, and develop peptide based compounds targeting this interaction for use as therapeutics or more likely as a lead compound for further development of small molecule compounds for use as therapeutics. Excitingly, these studies enabled us to develop a series of compounds which were as if not more effective at arresting/reversing the rate of leukocyte mediated killing of endothelial cells in an ex vivo cell-based assay than full length NIF. 

Key in interpreting these results is an X-ray crystal structure of NIF (of which none currently exists nor that of a homologous protein) as well as a complex structure between NIF and its cellular target. This proposal will employ a summer student to express NIF and attempt its crystallization. Previous summer and capstone students have made progress in this area with the last student producing putative crystals which are slated for study at the Synchrotron on our next trip. Continued efforts towards purification and crystallization will be required to produce diffraction quality crystals needed for structure determination.

David Lodowski, PhD


Antioxidant Independent Functions of Vitamin E

Novel, antioxidant-independent functions of Vitamin E

Alpha-tocopherol (vitamin E) is an essential nutrient and a major fat-soluble antioxidant in humans; vitamin E deficiency causes severe pathologies in humans, primarily affecting the central nervous system. The vitamin’s health-promoting actions have been attributed to its antioxidant function, i.e. its ability to protect biological membranes from oxidative stress. Although the importance of the vitamin’s antioxidant activity has been established decades ago, others and we have suggested that α-tocopherol has additional, antioxidant-independent activities, for example in regulating gene expression. We recently designed, synthesized, and employed a novel analog of vitamin E (6-HMTC) that is structurally very similar to alpha-tocopherol, yet is not a functional antioxidant. We found that while 6-HMTC behaved in an identical manner to alpha-tocopherol in important biochemical end-points (i.e. high-affinity binding to its transport protein), it lacks any detectable antioxidant activity in vitro and in vivo. Surprisingly, we found that 6-HMTC and alpha-tocopherol are equally effective in modulating gene expression. These data indicate that the health promoting actions of vitamin E involve novel, previously un-appreciated functions that do not involve the molecule’s antioxidant function. The Wharton fellow will examine the molecular mechanisms by which this phenomenon occurs, and examine the role of this activity in CNS health in a genetic mouse model of vitamin E deficiency. 

Danny Manor, PhD


DICE

Diabetes Inspired Culinary Education (DICE)

While Type I Diabetes Mellitus (TIDM) accounts for only 5% of the diabetic population in the U.S., the prevalence of this lifelong, taxing autoimmune disease has been steadily rising over the past two decades.  Due to the complex nutritional nature of the disease and the direct link between food consumption and blood glucose levels, consuming a well-balanced diet is vital for the short- and long-term health outcomes of individuals with TIDM. However unfortunately, while feeding issues, such as food neophobia and picky eating, are common among all youth, the prevalence of feeding issues is exceptionally high among youth with TIDM due to the complex nutritional nature of TIDM.  As a result of these additional barriers, youth with TIDM consistently have a poorer diet quality than their healthy counterparts, which can lead to detrimental consequences with disease management, as well as growth and development. 

Culinary medicine is an area of research that is still in its infancy, however initial studies have demonstrated success in improving diet quality and decreasing feeding issues among youth through culinary medicine. Early studies have also demonstrated a positive association between child food preparation skills/frequency of involvement and an array of non-dietary child health outcomes (e.g., disease management, academic performance, mental health). Furthermore, culinary medicine interventions targeting adults with Type II Diabetes Mellitus have produced positive, lasting dietary and diabetes management outcomes. However, despite the great potential for using culinary medicine to elicit positive behavior change amongst youth with TIDM, to our knowledge, this area of research is yet to be explored.  Therefore, this pilot research project aims to develop and assess the effectiveness of a culinary medicine program (Diabetes Inspired Culinary Education, DICE) on improving diet quality and diabetes management among 6-14 year old children with TIDM. The aims of this pilot study are to:

  1. Develop a sustainable referral and recruitment mechanism between the Northeast Ohio Chapter of the Juvenile Diabetes Research Foundation and CWRU Nutrition Department to enroll eligible families in the DICE program.  
  2. Evaluate the feasibility of implementing the community-based DICE program by assessing process level outcomes 
    • Outcomes to be assessed: recruitment rates, participant attendance, retention rates, dropout rates 
  3. Evaluate the effectiveness of the community-based DICE program at the child-level by assessing child level outcomes  
    • Outcomes to be assessed: dietary intake; biometric markers (HbA1c); anthropometrics; food preparation skills and frequency of involvement
  4. Evaluate the effectiveness of the community-based DICE program at the caregiver-level by assessing caregiver level outcomes
    • Outcomes to be assessed: dietary intake; anthropometric outcomes; self-efficacy; food preparation skills and frequency
  5. Evaluate the effectiveness of the community-based DICE program at the family-level by assessing family level outcomes  
    • Outcomes to be assessed: family meal frequency; family meal environment; psychosocial markers

Catherine Rogers, PhD, RDN, LD


Treatment Expectations for Severe Obesity, Qualitative

Treatment expectations of adolescents with severe obesity

Currently, weight loss surgery is the only intervention that has shown to be effective in producing clinically significant weight loss for adolescents with severe obesity. This may be due to 1) higher than average attrition of adolescents with severe obesity from lifestyle intervention programs when compared to their peers with moderate obesity, and 2) lack of aggressive, non-surgical treatment options offered to adolescents with severe obesity in clinical weight management settings. Both of these issues may be addressed by better understanding the expectations and desires of adolescents with severe obesity as they enter treatment. Although research on expectations for obesity treatment has been conducted previously, most studies are quantitative in nature, focus only on the opinion of the parent, and/or are not specific to severe obesity. Additionally, these studies have focused on conservative lifestyle interventions without giving participants the opportunity to comment on their expectations and desires for more aggressive treatment options. The research proposed here will qualitatively assess the expectations and desires of treatment-seeking adolescents with severe obesity. Specifically, we will assess the range of interventions and outcomes that treatment-seeking 16-19 year old adolescents with severe obesity want and expect, as well as the language used by adolescents with severe obesity when discussing obesity treatment and outcomes. The long-term goal is to use the qualitative data to develop and validate a quantitative questionnaire that can be used in clinical and research settings to better understand treatment expectations.

Rosanna Watowicz, PhD, RDN, LD


Estrogen Receptor Misshaping

An emerging phenomenon of structural disorder in estrogen receptor

More than one third of the proteins that exist in humans are unstructured or disordered like a partially cooked spaghetti jiggling in a pot of boiling water. One exemplary protein disorder is the estrogen receptor transactivation domain, called ER-NTD, critical for recruiting coactivator proteins in gene activation that is hormone-independent and for breast cancer endocrine resistance. Very recently, we have shown that the ER-NTD is structurally disordered, yet unexpectedly compact and more importantly, forms metastable contacts in regulating the protein function (https://doi.org/10.1016/j.str.2018.10.026; see the preprint at http://dx.doi.org/10.1101/332205 before its publication on Dec. 20, 2018). The emerging concept of “contact metastability” we have established offers more than startling new insights into the basic biology of cells controlled by disordered proteins and equally exciting, provides new ways for treating diseases, including drug-resistant breast cancer in the case of ER-NTD.
         
Currently, two distinctive aspects of the ER-NTD contact metastability are being investigated in the lab. One is related to drug-resistant biomarkers (i.e., phosphorylation of residues Ser118 and Ser167), in which we aim to determine the extent to which the serine phosphorylation influences a set of specific NTD sites that are the potential target of interest. The other is on the impact of coactivator binding on the contact metastability, as demonstrated in our preliminary studies that the coactivator binding induces considerably large-scale conformational changes with a modest binding affinity.

Lastly, the lab has a history of hosting quite a few of CWRU undergraduate students. Productively, two recent students who have actively been working on the ER-NTD project became co-authors of our recent publication; one of them has moved on for her PhD study in San Diego. Of note, these research experiences have played an important, critical role in the admission into their post-undergraduate program.

Sichun Yang, PhD