The applicant for this K23 Mentored Patient-Oriented Research Career Development Award is a physician scientist with a focus on developing improved care for patients with sickle cell disease (SCD). Chronic kidney disease is present in a large proportion of adults with SCD and is associated with morbidity and early mortality. However, the pathways for sickle nephropathy are unfortunately poorly understood. This proposal will leverage robust genomic strategies to innovatively address mechanistic pathways and susceptibilities for chronic kidney disease in patients with SCD. The underlying hypothesis is that genetic variation existing outside the -globin gene-like cluster is centrally involved in influencing the propensity to develop chronic kidney disease. The applicant will apply exciting preliminary data to develop a candidate gene approach and mechanistic pathways to test this hypothesis via three specific aims.
Specific aim #1 will utilize a genomic approach to identify polymorphisms and expression quantitative trait loci (eQTL) in candidate genes to highlight functional pathways for chronic kidney disease in SCD.
Specific aim #2 will determine whether the identified gene variants are associated with the progression of chronic kidney disease in a longitudinal cohort to help recognize high-risk SCD patients for kidney disease and guide earlier intervention strategies.
Specific aim #3 will investigate mechanisms for understanding how variants in APOL1 and HMOX1 contribute to sickle cell nephropathy. With the guidance of a strong team of mentors, this proposal includes a comprehensive development program incorporating training opportunities through the University of Illinois at Chicago (UIC) School of Public Health, UIC Center for Clinical and Translational Sciences Program, and Department of Medicine. The goals of this proposal are to enhance the applicant's career development and skills in bioinformatic, biostatistical, and translational methods in order to conduct research for understanding the pathobiology of kidney disease in patients with SCD. The applicant is exceptionally positioned to achieving the goals outlined in this proposal through a strong history of productivity and the institutional environment which includes the UIC Comprehensive Sickle Cell Center which cares for over 800 SCD patients and has a long-standing tradition of successful implementation of clinical studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population and will facilitate the long-term goals of the applicant in becoming a successful and independent translational researcher focusing on sickle cell nephropathy.

Public Health Relevance

Sickle cell disease is among the most common monogenetic diseases worldwide and chronic kidney disease, which occurs in more than half of adults with sickle cell disease, is associated with high mortality. Through the mentored K23 award, the goals of this proposal are to identify genetic variants in functional pathways for chronic kidney disease in patients with sickle cell disease. We hope that these findings will facilitate future development of interventional strategies to prevent and treat sickle nephropathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL125984-04
Application #
9485998
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Werner, Ellen
Project Start
2015-09-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Saraf, Santosh L; Sysol, Justin R; Susma, Alexandru et al. (2018) Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. Transl Res 197:1-11
Han, Jin; Zhou, Jifang; Kondragunta, Vinod et al. (2018) Erythropoiesis-stimulating agents in sickle cell anaemia. Br J Haematol 182:602-605
Zhou, Jifang; Han, Jin; Nutescu, Edith A et al. (2018) Hydroxycarbamide adherence and cumulative dose associated with hospital readmission in sickle cell disease: a 6-year population-based cohort study. Br J Haematol 182:259-270
Han, Jin; Zhang, Xu; Saraf, Santosh L et al. (2018) Risk factors for vitamin D deficiency in sickle cell disease. Br J Haematol 181:828-835
Saraf, Santosh L; Oh, Annie L; Patel, Pritesh R et al. (2018) Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease. Biol Blood Marrow Transplant 24:1759-1765
Saraf, Santosh L; Viner, Maya; Rischall, Ariel et al. (2018) HMOX1 and acute kidney injury in sickle cell anemia. Blood 132:1621-1625
Gallo, Agatha M; Patil, Crystal; Adeniyi, Tokunbo et al. (2018) Health-Related Quality of Life and Personal Life Goals of Adults With Sickle Cell Disease After Hematopoietic Stem Cell Transplantation. West J Nurs Res :193945918768277
Han, Jin; Saraf, Santosh L; Kavoliunaite, Laura et al. (2018) Program expansion of a day hospital dedicated to manage sickle cell pain. Am J Hematol 93:E20-E21
Raslan, Rasha; Shah, Binal N; Zhang, Xu et al. (2018) Hemolysis and hemolysis-related complications in females vs. males with sickle cell disease. Am J Hematol 93:E376-E380
Jerebtsova, Marina; Saraf, Santosh L; Soni, Simran et al. (2018) Urinary orosomucoid is associated with progressive chronic kidney disease stage in patients with sickle cell anemia. Am J Hematol 93:E107-E109

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