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Bertal Huseyin Aktas, DVM, , Ph.D.
Scientist, Brigham and Women's Hospital
Assistant Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Hematology
75 Francis Street
Boston, MA 02115


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Research Narrative:
As a researcher, my major commitment is to investigate cellular proliferation and transformation, and molecular and chemical genetics of the integrated endoplasmic reticulum stress response (IERSR). Cellular proliferation and transformation. Origins of this research lay in my discovery that Cyclin D1 and p27Kip1 link Ras signaling to cell cycle machinery. Ras, activated in 15-20% of human cancers, interacts with translation initiation factors in a feed-forward loop to increase expression of oncogenic proteins at the level of translation. The realization that translation initiation is at the apex of many oncogenic pathways prompted me to test the hypothesis that translation initiation factors can be targeted for cancer therapy. My collaborators and I have identified several small molecule translation initiation inhibitors using high throughput assays. These include diaryl-oxindoles, thiozolidones, and N,N’-diarylureas that inhibit eIF2.GTP.met-tRNAi ternary and thiozolidonehydrozone-based agents that inhibit eIF4F translation initiation complex. I also developed assays to accredit the in vivo mechanism of action and the specificity of these agents. In the course of these studies I identified heme regulated inhibitor kinase as a novel target for cancer therapy. These studies are currently supported by an RO1 and an industry grant on which I am the Principal Investigator. Molecular and chemical genetics of the IERSR. The IERSR maintains a balance between demand and capacity for folding newly synthesized proteins. Defects of the IERSR are associated with multiple human disorders, including cancer, and neuro-degeneration. That the eIF2.GTP.met-tRNAi is a critical component of the IERSR prompted me to study the molecular and chemical genetics of the IERSR. My group utilized high throughput assays to screen whole-genome human siRNA and small molecule libraries and identified unique genetic and chemical modifiers of the IERSR. I will capitalize on these probes to study biology of endoplasmic reticulum and delineate the role of IERSR in the pathobiology of human disorders, particularly cancer. In collaboration with leading experts, I will attempt to delineate the role of the IERSR in the pathobiology of the motor-neuron diseases. Both RO1 and R21 grant applications to support these work are at various stages of review process.

Education:
University of Wisconsin, 1994
Istanbul University, 1985, DVM

Publications (Pulled from Harvard Catalyst Profiles):

1. Liu F, Dai S, Feng D, Peng X, Qin Z, Kearns AC, Huang W, Chen Y, Ergün S, Wang H, Rappaport J, Bryda EC, Chandrasekhar A, Aktas B, Hu H, Chang SL, Gao B, Qin X. Versatile cell ablation tools and their applications to study loss of cell functions. Cell Mol Life Sci. 2019 Jul 29.

2. Aktas BH, Upcin B, Henke E, Padmasekar M, Qin X, Ergün S. The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells. Stem Cells Int. 2019; 2019:1608787.

3. Persaud L, Mighty J, Zhong X, Francis A, Mendez M, Muharam H, Redenti SM, Das D, Aktas BH, Sauane M. IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells. Int J Mol Sci. 2018 Nov 12; 19(11).

4. Nandigama R, Upcin B, Aktas BH, Ergün S, Henke E. Restriction of drug transport by the tumor environment. Histochem Cell Biol. 2018 Dec; 150(6):631-648.

5. Zhong X, Persaud L, Muharam H, Francis A, Das D, Aktas BH, Sauane M. Eukaryotic Translation Initiation Factor 4A Down-Regulation Mediates Interleukin-24-Induced Apoptosis through Inhibition of Translation. Cancers (Basel). 2018 May 22; 10(5).

6. Machado FC, Franco CH, Dos Santos Neto JV, Dias-Teixeira KL, Moraes CB, Lopes UG, Aktas BH, Schenkman S. Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation. Sci Rep. 2018 Mar 20; 8(1):4857.

7. Bahnan W, Boucher JC, Gayle P, Shrestha N, Rosen M, Aktas B, Adkins B, Ager A, Khan WN, Schesser K. The eIF2a Kinase Heme-Regulated Inhibitor Protects the Host from Infection by Regulating Intracellular Pathogen Trafficking. Infect Immun. 2018 03; 86(3).

8. Dias-Teixeira KL, Calegari-Silva TC, Medina JM, Vivarini ÁC, Cavalcanti Á, Teteo N, Santana AKM, Real F, Gomes CM, Pereira RMS, Fasel N, Silva JS, Aktas BH, Lopes UG. Emerging Role for the PERK/eIF2a/ATF4 in Human Cutaneous Leishmaniasis. Sci Rep. 2017 12 06; 7(1):17074.

9. Burwick N, Aktas BH. The eIF2-alpha kinase HRI: a potential target beyond the red blood cell. Expert Opin Ther Targets. 2017 12; 21(12):1171-1177.

10. Yefidoff-Freedman R, Fan J, Yan L, Zhang Q, Dos Santos GRR, Rana S, Contreras JI, Sahoo R, Wan D, Young J, Dias Teixeira KL, Morisseau C, Halperin J, Hammock B, Natarajan A, Wang P, Chorev M, Aktas BH. Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2a) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response. J Med Chem. 2017 07 13; 60(13):5392-5406.