BSCD Summer Undergraduate Research Fellowship in Pathophysiology, Biology, and Bioenergetics of Kidney Diseases - 2025
Summer Undergraduate Research Fellowship in Pathophysiology, Biology, and Bioenergetics of Kidney Diseases
Summer Research Program Description:
The Summer Undergraduate Research Fellowship in Pathophysiology, Biology, and Bioenergetics of Kidney Diseases takes advantage of the breadth and depth of the Departments of Medicine, Pathology and Radiology within the Sections of Nephrology, Genetics, Oncology and Physics. With a focus on common kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) (Drs Chapman, Chen, Faubert and Hanlon), nephrolithiasis (Drs Worcester, Reynolds and Prochaska), diabetic kidney disease (Dr. Mirmira), proteomic/transcriptomioc analyses (Drs Chapman, Chen and Hanlon) , and kidney imaging involving radiomics, texture analysis and artificial intelligence (Drs Armato, Chapman and Kremer) summer fellows will learn about the kidney ‘s role in homeostasis and regulation/handling of key components of metabolism, mechanisms of urinary acidification, impact of the microbiome, bioenergetic regulation by the kidney in general and as it relates to sleep disorders, and imaging and textural analyses including magnetic resonance fingerprinting. These programs will provide summer fellowship students with an introduction to the field of renal physiology, circadian biology, medical physics and cellular biology including proteomic and transcriptomic expression at the single cell level of renal tubular epithelial cells in the context of common kidney disorders. This program is a small group experience (2-3 students/lab) with the opportunity for active and individual mentoring. The curriculum includes: 1) Attendance and participation in daily mid-day 50 minute lectures reviewing components of kidney function, physiology and molecular genetics, and metabolism with a focus on ADPKD, nephrolithiasis, metabolism and disorders of circadian biology with the opportunity to discuss these topics with experts in the field 2) Attending weekly academic conferences within the Section of Nephrology held at 4 pm on Thursdays and noon Fridays 3) Participation in the assigned mentor lab with daily lab work focusing on the student project and general meetings held at least twice a week 4) Participation in the summer principals of medical physics and radiomics (Drs. Armato and Kremer) 5) Shadowing expert clinicians in their weekly outpatient clinics on Tuesdays and Wednesdays (Drs Prochaska, Worcester, Zisman and Chapman) to observe patients with underlying kidney problems that are the focus of the research studies in their respective labs 6) Observe and potentially participate in human subject research including overnight sleep studies on the Clinical Research Center which is a research-only inpatient and outpatient ward studying research participants suffering from chronic kidney disease. There is an every other week seminar held during the fellowship, with presentations of ongoing work by the summer fellows with their faculty mentors. This seminar is led by the Chief of Nephrology, Dr. Arlene Chapman along with the faculty mentors. Students will briefly discuss the overall progress in their lab and highlight his/her own summer project. This will give the students the opportunity to present their progress to each other throughout the fellowship. This will be a wonderful opportunity for this summer’s fellowship cohort. Overall, it is expected that the students in this program will be deeply immersed in their projects during the summer and as time permits throughout the rest of the academic year.
Requirements:
1. Required skills:
- Excellent written, verbal communications and analytical skills
- Ability to work as a team member
- Ability to manage time efficiently, multi-task and prioritize
- Self-directed and able to work independently with faculty support
- Proficient computer skills, including Microsoft Office Suite
2. Required Materials
- Resume or CV
- Cover Letter/Statement of Interest
Please submit all materials as PDF files.
NOTE: Students should identify the project(s) in which they are interested in their Cover Letter / Statement of Interest. Fellowship recipients will be paired with a faculty mentor based on availability.
Application Expiration Date:
Applications must be submitted by April 7, 2025.
Interviews:
Interviews may be requested.
Please Note: If you are applying to multiple BSCD Fellowship Grants, please fill out the following BSCD Preference Form - https://careeradvancement.wufoo.com/forms/bscd-research-2025/
Potential Mentors:
- Arlene Chapman, MD, Professor of Medicine, Chief of Nephrology
- Peili Chen, PhD, Research Associate
- Brian Faubert, PhD
- Erin Hanlon, PhD
- Elaine Worcester, MD, Professor of Medicine
- Megan Prochaska, MD, Assistant Professor of Medicine
- Luke Reynolds, MD. Assistant Professor of Surgery
- Dr. Sam Armato, Professor of Radiology
- Dr. Linnea Kremer
Description of Projects:
Project # 1:
Title: Targeting Amino Acid Metabolic Crossroads in ADPKD
Mentors: Arlene Chapman, MD, Peili Chen, PhD, Brian Faubert, PhD, Departments of Medicine and Molecular Biology. Drs. Chapman, Faubert, and Chen will be available and committed to fully mentor students, including guidance about overall career development.
Project description
Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disease, is caused by mutations in the PKD1 or PKD2 gene which encode polycystin-1 and polycystin-2 transmembrane heterodimer proteins. Multiple signaling pathways are affected by mutated polycystin1 and polycystin2, including primary ciliary signaling and Ca2+/cAMP cascade that contribute to the abnormal proliferation of epithelial cells and cyst formation in ADPKD. Initiated in early childhood, progressive enlargement of kidney cysts damages kidney structure and function, eventually leading to kidney failure typically in the 5th to 6th decade of life. Despite promising results from recent studies and trials, therapies that cure or slow the progression of disease are limited. The slow progressive nature of ADPKD makes it difficult to diagnose and treat at early stage as kidney function or estimated glomerular filtration rate (eGFR) is normal for decades. Height corrected total kidney volume (htTKV), an accurate and reproducible FDA approved prognostic imaging biomarker can increase several-fold prior to loss of kidney function and represents kidney cyst burden and epithelial proliferation.
Increasing understanding of the signaling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of cancers at the cellular and molecular level. ADPKD shares most of cancer hallmarks including sustained proliferative signaling, evasion of growth suppressors, induction of angiogenesis, deregulation of cellular energetics, tumor promoting inflammation, genomic instability and mutation and abnormally reprogrammed metabolism. Metabolic reprogramming provides energy and substrates that is necessary to support tumor growth, survival, immune evasion, and metastasis. Recent studies in PKD1 cystic epithelial cells demonstrate a Warburg-like effect as observed in cancer cells, which when inhibited results in inhibited cell proliferation and decreased cyst growth and an increase in htTKV. These metabolic changes are also present in plasma and urine from ADPKD patients, indicating altered bioenergetics and adaptation supporting a proliferative cystic phenotype in ADPKD.
We have demonstrated comprehensive abnormalities in multiple amino acid concentrations and metabolic pathways in our studies in urine and plasma in ADPKD patients with normal kidney function, particularly the histidine pathway. Furthermore, levels of histidine metabolites correlate with cyst burden (htTKV) and kidney function (eGFR). In ADPKD cyst fluids, concentrations of all amino acids, except for glutamine and proline, are elevated compared to those in plasma and urine, with an accumulation of amino acids on the apical surface of cystic epithelia. Pharmacologically, histidine metabolism involving histidine decarboxylase or histidine ammino-lysase affects human kidney PKD1 cystic cell proliferation but not healthy human kidney epithelia, indicating a possible therapeutic role in the treatment of this disorder.
Through prior Summer Undergraduate Research Fellowship programs, iPSCs (pluripotent stem cells) have been derived from urinary epithelial cells from PKD1 and PKD2 patients. We now can differentiate these iPSCs to human kidney organoids and human kidney tubuloids. These models will be used to address the differential impact of amino acid bioavailability, exposure to hypoxia and hypertonicity, features to the microenvironment in the kidney. Given the genetic clonality of cystic epithelial, single cell rna seq of primary human cystic epithelia will be performed.
Specific Aims
To determine the effects of loss of the PKD1 or PKD2 genes on amino acid metabolism, transport and flux.
Approach and Methods
1. To investigate amino acid homeostasis by evaluation of histidine transporters in small intestinal epithelia, hepatocyte and renal cystic (PKD1 or PKD2 mutations) compared to normal non-cystic epithelia. Expression and function of histidine transporters will be studied in tissues and specific cell types including resident macrophages, fibroblasts, cystic and non-cystic epithelial cells harvested from genetically modified mice using immunostaining and affinity assays.
2. To characterize histidine and its metabolic flux into different pathways in PKD1 and PKD2 knockdown cells established by siRNA using stable isotopic 13C-histidine.
3. To define difference in energy production from histidine in PKD1/PKD2 cells compared to normal non-cystic controls under controlled environmental conditions including cell starvation, hypoxia, histidine and glutamine deprivation.
4. To determine metabolic flux of isotopically labelled glucose, lactate and glutamine in human cystic epithelial cells.
4. To utilize human iPSCs derived from urinary epithelial cells to develop kidney organoids and tubuloids to test differences in amino acid bioavailability, hypoxia and hypertonicity as critical regulators of cyst proliferation and growth as well as determining single cell transcriptomic changes.
Project # 2: Dr. Sam Armato (Department of Medical Physics), Dr. Arlene Chapman (Section of Nephrology) and Dr. Linnea Kremer, (Department of Medicine)
Title: Investigation of MRI pre-processing and the effect on radiomic features and classification performance of PKD1 and PKD2 ADPKD patients
Mentors: Linnea Kremer, Sam Armato, Arlene Chapman
Project Description
Currently, height-corrected total kidney volume (htTKV) is an FDA approved biomarker for monitoring autosomal dominant polycystic kidney disease (ADPKD) progression, using height-corrected total kidney volume, age and gender as a measure of disease severity. Although this method has been crucial monitoring ADPKD patients, htTKV alone does not capture quantifiable data such as non-cystic kidney tissue which is known to be damaged by the adjacent cysts. Radiomics is an emerging field of translating medical images into quantitative, mineable data using image features for underlying biological information. However, the field of radiomics lacks a standardized approach of analyzing medical images across diseases and imaging modalities. Furthermore, some contrasts in MRI have arbitrary signal intensities and benefit from image normalization when extracting radiomic texture features for both inter- and intra-patient comparisons. Radiomics pre-processing is a mandatory step in analyzing and calculating texture features from medical images. There are different pre-processing steps (image normalization, resampling voxel size, discretization of gray-level histogram), but the effect of these parameters on downstream classification has not been evaluated thoroughly. These questions are related to larger research using MRI radiomics analysis for diagnosis, prognosis, and assessment of disease progression in ADPKD at the University of Chicago.
This work will further texture-based imaging biomarkers for a deeper understanding of differences in kidney tissues (non-cystic tissues adjacent to kidney cysts) between PKD1 and PKD2 ADPKD genotypes. Currently, there is limited research on texture-based imaging biomarkers of ADPKD MRI. Previous research has shown image texture to predict kidney function decline. In addition, combining image features and clinical information for modeling of ADPKD disease had a stronger predictive performance than image or clinical modeling alone. PKD2 patients overall demonstrate milder kidney disease, with 40% fewer cysts, delayed onset of hypertension, and longer patient and kidney survival. PKD1 patients reach end-stage kidney disease (ESKD) about two decades earlier than PKD2. Therefore, investigating image features to classify ADPKD genotype (PKD1 vs. PKD2) is of much interest to better understand biologic differences in genotype expression in kidney MRI.
A recent pilot study showed a combination of texture features of the non-cystic parenchyma successfully differentiated between PKD1 and PKD2 ADPKD patients using a linear discriminant analysis (LDA) classifier. In addition, our work showed that of the 93 features calculated, only 17 were reliable across two different reference-tissue using z-score normalization. This work will be continued on a larger dataset using the HALT-PKD study of 558 hypertensive ADPKD patients to compare PKD1 and PKD2 non-cystic parenchyma. Normalization and pre-processing of the images are necessary for our radiomics analysis, and different parameters will be analyzed to standardize a radiomics pipeline of ADPKD MRI. In addition to this research opportunity, the Committee on Medical Physics will provide a summer course on the physics of medical imaging.
Specific Aims
1. Identify stable radiomic texture features that may classify between PKD1 and PKD2 and relate that to genotype expression.
2. Quantify the differences in performance of MRI pre-processing methods in PKD1 and PKD2 classification.
3. Determine the added value of integrating texture and MR fingerprinting values, a measure of tissue energy, in ADPKD kidneys
Approach and Methods
1. Calculate radiomic texture features of the non-cystic parenchyma of PKD1 and PKD2 patients using different pre-processing parameters using an open-source software, Pyradiomics.
2. Use a classifier to differentiate between PKD1 and PKD2 non-cystic radiomic features across different pre-processing methods.
3. Compare the performance of the classifier across pre-processing methods using statistical analysis.
Skills learned
Fundamental principles of MRI physics, coding, data/statistical analysis, MRI characteristics of ADPKD, radiogenomics
Project # 3:
Title: Diet Acid-Base Balance in Patients with Calcium Kidney Stone Disease
Mentors: Elaine Worcester, MD, Luke Reynolds, MD, Megan Prochaska, MD, Anna Zisman, MD. Departments of Medicine and Surgery. Drs. Worcester, Reynolds, Zisman and Prochaska will be available and committed to fully mentor the students, shadowing in outpatient clinic and guidance about overall career development.
Project Description
Diet sodium and acid intake strongly affect mineral metabolism and risk for kidney stone formation. Acid loads raise urine calcium losses, saturating urine with stone forming calcium salts, and foster bone mineral loss. The effects are most severe in those people with inherited hypercalciuria, a polygenic trait that makes calcium balance and urine calcium loss abnormally responsive to both salt and acid load. We have found that patients who make calcium phosphate stones, and women who make calcium oxalate stones, have abnormalities of acid-base status, compared to same-sex normal subjects. We have also discovered differences in acid-base handling that involve both gastrointestinal system and kidney in normal men and women. Funded by an NIH Program Project grant (Worcester, PI) the group presently studies effects of varying diet sodium and alkali supplementation on renal calcium handling in the University of Chicago Clinical Research Center.
A full understanding of acid-base balance requires a complete accounting for all renal acid excretion, which is not obtainable from standard urine measurements. In order to better understand the abnormalities we have seen in various types of stone formers, as well as the differences in acid-base handling between normal men and women, we have added novel measurements of urine anion excretion that are the effectors of acid production from diet. We are studying these anions in response to altered diet sodium and alkali, in both types of calcium stone formers and normal subjects. To complement our new measurements, we plan metabolomic measurements of urine anion patterns in collaboration with Dr. Arlene Chapman’s group.
Our previous work has shown differences in segmental renal tubule handling of sodium and calcium between normal subjects and stone formers, which foster loss of calcium in the urine. As there is no appropriate animal model of human stone formation, it has been difficult to examine the possible differences in renal tubule transporter abundance or function that may create the altered mineral handling. Dr. Ko has recently applied the techniques of urine exosome analysis to characterize how nutrient ingestion alters renal transporters, by measuring the levels of transporters of interest in urine exosomes during nutrient challenges.
Specific Aims
1. Identify and quantify the differences in renal tubule sodium and calcium handling between calcium stone formers and normal subjects under conditions of high and low salt intake, with or without alkali.
2. Quantify the differences in renal tubule transporter abundance between calcium stone formers and normals under conditions of high and low salt intake, with or without alkali.
3. Quantify the differences in acid-base handling between normal subjects and calcium stone formers using standard
Approach and Methods
1. Calculate proximal and distal nephron sodium and calcium reabsorption using endogenous lithium clearance in normal men and women and in men and women with calcium oxalate or calcium phosphate stones on each of 4 diets. Diets will be low sodium or high sodium, with 20 meq potassium citrate daily or placebo, in random order.
2. Measure urine exosome levels of NHE3, SLC26A6, claudin 2, NKCC2, Claudin 14, NCC, TRPV5 and prostasin in patients in aim 1.
3. Measure urine markers of acid and alkali balance and urine organic anions by titration, in stone formers and normal subjects, and calculate acid balance.