Student Successfully Defends Dissertation

Jenny Lutshumba from Gong Lab successfully defended her dissertation and earned her doctoral degree Friday, February 10, 2017.

Committee Members
Dr. Ming Cui Gong
Mentor, Department of Physiology

Dr. David Randall
Department of Physiology

Dr. Zhenheng Guo
Department of Pharmacology & Nutritional Sciences

Dr. Alan Daugherty
Department of Physiology

Former Committee Member
Dr. Karyn Esser
Department of Physiology

Outside Examiner
Dr. Victoria King
Department of Pharmacology & Nutritional Sciences

Abstract of Dissertation
Abdominal aortic aneurysm (AAA) is a devastating condition that occurs primarily among older people with high mortality when a rupture occurs. Currently there is no proven pharmacological therapy for AAA due to poor understanding of the underlying pathogenesis. The brain and muscle transcription factor ARNT-like (Bmal1), which is known to regulate circadian rhythm, has been implicated in vascular pathologies including atherosclerosis and vascular remodeling, but its role in AAA has not been explored.

Vascular smooth muscle is a central player in aneurysm formation and development because it is critical in all three aortic aneurysm hallmark processes including (a) degradation of elastin and extracellular matrix protein, (b) loss of medium layer smooth muscle cells, and (c) intense inflammatory cell infiltration.

Here we report that smooth muscle-selective deletion of brain and muscle Arnt-like protein-1 (Bmal1) potently protected mice from AAA induced by mineralocorticoid receptor (MR) agonist deoxycorticosterone acetate (DOCA) or Angiotensin II (ANG II) in the presence of high salt. Bmal1 was upregulated by DOCA-salt in the aorta. Moreover, deletion of Bmal1 in smooth muscle selectively upregulated tissue inhibitor of metalloproteinase 4 (TIMP4) and also abolished DOCA-salt-induced elastin degradation and matrix metalloproteinase (MMP) activation. Mechanistically, Bmal1, when bound to TIMP4 promoter, suppressed the transcription of the promoter. Taken together, these results reveal an important but previously unexplored role of smooth muscle Bmal1 in DOCA plus salt-induced AAA. We suggest that TIMP4 constitutes a novel therapeutic target for AAA treatment.

Acknowledgements
First and Foremost, I would like to thank my mentor Dr. Ming Gong for welcoming me into her lab and supporting me during the last few years. Dr. Gong had shown patience, motivation enthusiasm and immense knowledge. She pushed me into critical thinking and helped me improve my flaws. Her mentorship allowed me to grow as a research scientist. I will always be grateful for her support in my professional and personal life.

I am also grateful to each member of my committee: Dr. Alan Daugherty, Dr. Karyn Esser, Dr. Zhenheng Guo for their expertise and criticism which helped improved the quality of my project. I am grateful to Dr. David Randall for stepping in at the last minute as committee member and his editorial input. I also would like to thank Dr. Victoria King for agreeing to be the outside examiner for my dissertation defense. I am also grateful to Dr. Brian Finlin for his editorial input throughout the writing process of my dissertation. Finally, I thank Dr. Kenneth Campbell and Dr. Bret Smith for their advice and counsel.

I also would like to thank different members of Dr. Guo and Dr. Gong’s lab. Dr. Liu Shu, Dr. Wen Su, Tianfei Hou, and Zhang Ming, they all supported me throughout my study and they helped me in many of my experiments. Former Lab member: Dr. Zhongwen Xie and Dr. Guogang Zhao taught me molecular biology and helped facilitate some experiments.

I will never forgive myself if I did not thank my family. First, I would like to thank my husband for his love and support, my son for bringing a light into my life every time he smiles at me. I am also thankful for my father and my mother. Their support and prayers throughout this process has been very important to me.

Lastly, I would like to say a big thank you to my God. The Almighty God has always been with me since I started this program. He gave me strength when I was feeling weak. He guided me and brightened my path. To that I say: Glory be to God.