The overall goal of this project is to provide Dr. Osheiza Abdulmalik with strongly mentored scientific and intellectual training essential to his transition to an independent researcher in the field of molecular hematology. This training will be expertly guided by his primary mentor, Dr. J. Eric Russell, co-mentor Dr. Katherine High, and a highly-experienced Advisory Committee of accomplished investigators committed to training young investigators. Training will be facilitated by the active research environment and abundant support mechanisms available at the Children's Hospital of Philadelphia and the University of Pennsylvania. The proposed work is a direct extension of the applicant's recent project and focuses on gene variants responsible for hemoglobin disorders, which are among the most prevalent hereditary disorders worldwide. The long-term goal is to unravel the mechanism(s) responsible for the baseline stability of human beta-globin mRNA, and discover ways to manipulate transgenes to encode mRNAs with enhanced stabilities. These highly stable mRNAs would be expected to accumulate to high levels and translate substantial amounts of therapeutic protein for blood disorders, with emphasis on sickle cell disease and beta-thalassemia.
Three specific aims are designed to confirm and extend a substantial body of relevant preliminary data, as well as provide Dr. Abdulmalik a framework for developing skills critical to his eventual success as an independent investigator. His pilot data suggest that the stability of beta-globin mRNA can be enhanced in cultured cells by duplication of a stem-loop structure within its 3'untranslated region (3'UTR). The P.I. will extend this research by: 1) investigating and assessing the stabilities of variant human beta-globin mRNAs in vivo in stably-transfected cultured erythroid cells;2) establishing the autonomous functions of mRNA-stability enhancing beta-globin 3'UTRs in erythroid and non-erythroid cells, because autonomously functioning mRNA-stabilizing elements would hold tremendous additional value for other therapeutic transgenes;and 3) investigating key structural features of double-stem loop beta-globin 3'UTRs that may suggest a mechanism for its mRNA-stabilizing activity. The proposed research work, combined with the didactic training and structured mentoring will provide new insights into ways to manipulate mRNA stability to develop new therapies for hemoglobin disorders and will enable the P.I. to establish himself as a successful and productive independently funded researcher.

Public Health Relevance

Hemoglobins abnormalities cause some of the most prevalent inherited genetic disorders worldwide. Sickle cell disease and beta-thalassemia are two such serious disorders that continue to cause significant morbidity and mortality in the United States and globally. Our proposed research to investigate and develop new treatment options for the affected population is directly relevant to public health. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL103186-05
Application #
8657093
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Werner, Ellen
Project Start
2010-08-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$139,320
Indirect Cost
$10,320
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ghatge, Mohini S; Ahmed, Mostafa H; Omar, Abdel Sattar M et al. (2016) Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation. J Struct Biol 194:446-50
Zimmerman, Devon; Dienes, Jack; Abdulmalik, Osheiza et al. (2016) Purification of diverse hemoglobins by metal salt precipitation. Protein Expr Purif 125:74-82
Oder, Esther; Safo, Martin K; Abdulmalik, Osheiza et al. (2016) New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br J Haematol 175:24-30
Breda, Laura; Motta, Irene; Lourenco, Silvia et al. (2016) Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood 128:1139-43
Xu, Guoyan G; Deshpande, Tanvi M; Ghatge, Mohini S et al. (2015) Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry. Biochemistry 54:7178-92
Peranteau, William H; Hayashi, Satoshi; Abdulmalik, Osheiza et al. (2015) Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants. Blood 126:1245-54
Omar, A M; Mahran, M A; Ghatge, M S et al. (2015) Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents. Org Biomol Chem 13:6353-70
Zhang, Yujin; Berka, Vladimir; Song, Anren et al. (2014) Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression. J Clin Invest 124:2750-61
Nakagawa, Akito; Lui, Francine E; Wassaf, Dina et al. (2014) Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling. ACS Chem Biol 9:2318-25
Safo, Martin K; Ko, Tzu-Ping; Abdulmalik, Osheiza et al. (2013) Structure of fully liganded Hb ζ2β2s trapped in a tense conformation. Acta Crystallogr D Biol Crystallogr 69:2061-71

Showing the most recent 10 out of 17 publications