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The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells

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The Potential Detrimental Impact of Galactic Cosmic Radiation on Central Nervous System and Hematopoietic Stem Cells THE POTENTIAL DETRIMENTAL IMPACT OF GALACTIC COSMIC RADIATION ON CENTRAL NERVOUS SYSTEM AND HEMATOPOIETIC STEM CELLS By RUTULKUMAR UPENDRABHAI PATEL Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Scott M. Welford, Ph.D Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY January, 2019 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Rutulkumar Upendrabhai Patel Candidate for the Doctor of Philosophy degree *. (signed) Derek Taylor (Committee Chair) Scott M. Welford (Dissertation Advisor) Stanton L. Gerson (Committee Member) Marvin Nieman (Committee Member) Jennifer Yu (Committee Member) (date) December 3rd, 2018 *We also certify that written approval has been obtained for any proprietary material contained therein. ii Dedication I would like to dedicate this dissertation to my parents, Upendrabhai and Ujvalakumari Patel, who supported my wishes and ambitions despite being lived most of their lives in a lower-middle class family income. They sacrificed a lot to make sure a better life for their children. I would also like to dedicate this to my two sisters, Ekta and Vanita, for their support and encouragement over the years. iii Table of Contents Table of Contents ……………………………………………………………….. iv List of Figures ………………………………………………………………….. viii Acknowledgements ……………………………………………………………. xii Abstract ……………………………………………………………….…………. 1 Chapter 1: Introduction and Background ………………………………….. 3 1.1 Radiation, DNA Damage, and Carcinogenesis …………………………... 3 1.1.1 Space Radiation Environment and Induction of DNA Damage …………………………………………………………… 8 1.1.2 Radiation Induced Carcinogenesis ……………….................... 10 1.2 Hematopoietic Stem Cell Niche and Functions …………………………… 12 1.2.1 Low-LET Irradiation and HSC Injuries …………………………. 16 1.2.2 High-LET Irradiation Impact on HSCs …………………………. 17 1.3 Importance of Mismatch Repair ……………………………………………. 20 1.3.1 Compromised MMR and Cancer ………………….................. 25 1.3.2 MLH1, an Important MMR Component ………………………… 26 1.4 Radiation Exposure and Central Nervous System ……………………….. 27 1.4.1 Harmful Effects of Low-LET Irradiation on CNS ………………. 31 1.4.2 High-LET Irradiation Disrupts CNS functions …………………. 32 1.5 Statement of Purpose ……………………………………………………… 32 iv Chapter 2: Long-term deficits in behavior performances caused by low- and high-linear energy transfer radiation …………………….......................... 37 2.1 Abstract ………………………………………………………………………. 37 2.2 Introduction ………………………………………………………………….. 39 2.3 Materials and Methods ……………………………………………………… 41 2.4 Results ………………………………………………………………………... 46 2.5 Discussion ……………………………………………………………………. 50 2.6 Acknowledgements ……………………………………………................... 55 Chapter 3: MMR deficiency does not sensitize or compromise the function of hematopoietic stem cells to low and high LET radiation …………….. 64 3.1 Abstract ………………………………………………………………………. 64 3.2 Introduction …………………………………………………………………... 66 3.3 Materials and Methods ……………………………………………………… 69 3.4 Results ………………………………………………………………………... 72 3.5 Discussion ……………………………………………………………………. 78 3.6 Acknowledgements …………………………………………………………. 81 v Chapter 4: Mlh1 deficiency increases the risk of hematopoietic malignancy after simulated space radiation exposure ………………………………… 100 4.1 Abstract ……………………………………………………………………... 100 4.2 Introduction …………………………………………………………………. 102 4.3 Materials and Methods …………………………………………………….. 104 4.4 Results ………………………………………………………………………. 107 4.5 Discussion ………………………………………………………………….. 113 4.6 Acknowledgements ………………………………………………………… 117 Chapter 5: Age related loss of Mlh1 in hematopoietic stem cells accelerates tumorigenesis post simulated solar or galactic cosmic radiation exposure ………………………………………………………………………………………. 139 Chapter 6: Discussion and Future Directions ……………………………. 149 6.1 Tumorigenesis depends on LET of radiation source and Mlh1 status of HSCs ………………………………………………………………………………………. 152 6.2 Determine the impact of mixed beam GCR exposure on tumorigenesis of Mlh1 chimeric mouse model …………………………………………………………. 157 6.3 Define the mitigating potential of dietary polyamines as a countermeasure for GCR induced tumorigenesis …………………………………………………... 161 vi 6.4 Concluding Remarks ……………………………………………………... 163 References ……………………………………………………………………... 166 vii List of Figures Figure 1.1: Overview of DNA Damage, Repair Mechanisms, and Consequences …………………………………………………………………………………………. 6 Figure 1.2: Overview of Hematopoietic Stem Cell Niche Components and Hematopoiesis …………………………………………………………………… 14 Figure 1.3: Schematic Representation of Mismatch Repair Post Replication ………………………………………………………………………………………... 23 Figure 1.4: Symptoms and Timeline for the Development of IR-induced Brain Injuries …………………………………………………………………………….. 29 Figure 2.1: Diminished activity is a late toxicity from low- and high-LET radiation ………………………………………………………………………………………... 56 Figure 2.2: Long-term motor coordination defects were revealed after low- and high-LET radiation ……………………………………………………………….. 58 Figure 2.3: Low- and high-LET radiation cause long-term recognition memory loss ………………………………………………………………………………………... 60 Figure 2.4: Transient spatial memory loss is caused by γ-ray and 56Fe ion radiation ………………………………………………………………................................... 62 Figure 3.1: High LET radiation induces similar long term damage to the bone marrow as γ radiation ……………………………………………………………. 82 Figure 3.2: High LET radiation is more damaging to clonogenic capacity of stem cells than low LET radiation, but independent of MMR status ………………. 84 viii Figure 3.3: Blood counts demonstrate similar acute damage to the hematopoietic system across LET ………………………………………………………………. 86 Figure 3.4: Mlh1 knockout mice display enhanced sensitivity to IR ………………………………………………………………………………………... 88 Figure 3.5: Long term effects on hematopoiesis by IR is independent of MMR status ……………………………………………………………………………… 90 Figure 3.6: Defects in Mlh1 function do not enhance decreased competitive repopulation caused by IR ………………………………………………………. 92 Supplementary Figure 3.1: Myeloid CFU survival post radiation exposure ………………………………………………………………………………………... 94 Supplementary Figure 3.2: Lymphocyte counts in Mlh1+/+ and Mlh1-/- mice ………………………………………………………………………………………. 96 Supplementary Figure 3.3: Bone marrow cellularity in Mlh1+/+ and Mlh1-/- mice ………………………………………………………………………………………... 98 Figure 4.1: Long-term tumorigenesis assay post low- and high-LET radiation exposure ………………………………………………………………………… 119 Figure 4.2: Histopathology of tumors from Mlh1+/+ and Mlh1+/- mice ………………………………………………………………………………………. 121 Figure 4.3: Immunohistochemistry of lymphomas from Mlh1+/+ and Mlh1+/- mice ………………………………………………………………………………………. 123 ix Figure 4.4: Microsatellite instability found in Mlh1+/+ and Mlh1+/- tumors ………………………………………………………………………………………. 125 Figure 4.5: Whole exome sequencing analysis of Mlh1+/+ and Mlh1+/- TRB lymphomas ……………………………………………………………………… 127 Figure 4.6: Correlation between frequently mutated mouse TRB lymphoma genes vs human leukemia genes ……………………………………………………... 129 Supplementary Figure 4.1: HSC acute functional assays post radiation exposure ………………………………………………………………………………………. 131 Supplementary Figure 4.2: HSC differentiation independent of Mlh1 status ………………………………………………………………………………………. 133 Figure 5.1: 1H ion and 28Si ion irradiation affects HSC acute function, but not long- term differentiation ……………………………………………………………… 143 Figure 5.2: Incidence of tumorigenesis in Mlh1+/+ and Mlh1+/- mice post 1H ion and 28Si ion exposure ……………………………………………………………….. 145 Figure 5.3: Gene expression profile of Mlh1+/+ vs Mlh1+/- TRB lymphomas ………………………………………………………………………………………. 147 Figure 6: Summary explains the detrimental impact of GCR on mouse brain and hematopoietic stem cell ………………………………………………………... 150 Figure 6.1: The impact of LET and Mlh1 status on GCR induced tumorigenesis ………………………………………………………………………………………. 155 x Figure 6.2: Generation of Mlh1-/- chimeric mouse model and study of tumorigenesis …………………………………………………………………… 159 xi Acknowledgements I came to the United States in 2007 to pursue my career in the field of science and it was an exciting phase of my life to be in a vast country with plenty of opportunities around, but soon a honeymoon period was vanished and a real struggle began to find my place. Finding the first job was a really difficult task after graduating with Master’s degree and a minimal laboratory experience. At that time, Dr. Rajendra Mehta gave me an opportunity to kick start my career at IIT Research Institute, Chicago where I found my love for cancer research, and I knew that I had found my career path. The second opportunity was given to me by Dr. Nancy Oleinick at the CWRU, where she constantly supported and encouraged me to further pursue my education by getting into Ph.D. program. While working under excellent supervision of Dr. Oleinick, I met Dr. Scott Welford and came across a project funded by NASA, which immediately grabbed my attention. At that moment, I decided to pursue my Ph.D. under Dr. Welford’s mentorship. He taught me many lessons over the years but the importance of “asking the right question” to do a good science was the most insightful advice he ever gave me. Dr. Stanton Gerson, despite being extremely busy with multiple responsibilities, gave his precious time and advice throughout my journey. Dr. Derek Taylor, Dr. Marvin Nieman, and Dr. Jennifer Yu were very instrumental in providing new perspective and kept me on the track throughout
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