- NIH NINDS F30NS090714
- Title: ELUCIDATING A NOVEL MECHANISM FOR DEMENTIA
- Abstract: Dementia is a devastating clinical syndrome that affects millions of elderly individuals worldwide. Treating patients with dementia is challenging because of the myriad number of pathologies underlying its clinical manifestation and progression. Therefore, it is imperative to better understand the various mechanisms of dementia-inducing diseases in order to correctly diagnose and treat dementia patients. The focus of my proposed project is to study a common, but relatively underappreciated and under-studied, mechanism of dementia characterized by vascular abnormalities, hippocampal shrinkage, and abnormal protein accumulation (TDP-43) in the brain. Our lab has published several studies on two dementia-associated pathologies: hippocampal sclerosis of aging (HS-Aging) and brain arteriolosclerosis (B-ASC). HS-Aging is a common neurodegenerative pathology seen in up to 25% of individuals < 85 years at autopsy. B- ASC is a cerebrovascular pathology that increases in frequency and severity with advanced age. We have identified a common genetic risk variant in the ABCC9 gene with a polymorphism that changes risk for both B-ASC and HS-Aging pathologies. This phenomenon is exciting because it may point the way to a novel future therapeutic intervention related to ABCC9-modulating drugs. As a key step to better understanding the pathogenetic mechanism, new experiments are required. My overall hypothesis is that genetic and pharmacological perturbations in ABCC9 or its gene product lead to B-ASC pathology, which in turn, lead to HS-Aging/TDP-43 resulting in the clinical presentation of dementia. We will address this hypothesis through the following specific aims: 1) Test the hypothesis that a SNP, ABCC9.rs704180, is associated with altered vascular structure in aged individuals and 2) Test the hypothesis that chronic pharmacologic inhibition of ABCC9 gene product will cause B-ASC, thus in turn, exacerbating HS-Aging/TDP-43 pathology. In Aim 1, we will use human tissue samples from the University of Kentucky Alzheimer's Disease Center brain bio-bank to quantify vascular structures in individuals with varying ABCC9 SNP status. In Aim 2, we will treat mice with clinical and pathological HS-Aging characteristics (age-related TDP-43 pathology) to determine the effects of ABCC9 modifying drug treatment in these animals. Successful completion of this project will provide insight into a novel mechanism of dementia. In addition, it will provide opportunities for me to diversify my skillset as I prepare for a future career as a physician-scientist in the field of translational neuroscience research.
- 1. Nelson, P.T.;Wang, W.X.;Wilfred, B.R.;Wei, A.;Dimayuga, J.;Huang, Q.;Ighodaro, E.;Artiushin, S.;Fardo, D.W. "Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging." Journal of neurochemistry 134, 6 (2015): 1026-39.
- 2. Bachstetter, A.D.;Van Eldik, L.J.;Schmitt, F.A.;Neltner, J.H.;Ighodaro, E.T.;Webster, S.J.;Patel, E.;Abner, E.L.;Kryscio, R.J.;Nelson, P.T. "Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging." Acta neuropathologica communications 3, (2015): 32
- 3. Nelson, P.T.;Jicha, G.A.;Wang, W.X.;Ighodaro, E.;Artiushin, S.;Nichols, C.G.;Fardo, D.W. "ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target." Ageing research reviews (2015):
- 4.Ighodaro, E.T.;Jicha, G.A.;Schmitt, F.A.;Neltner, J.H.;Abner, E.L.;Kryscio, R.J.;Smith, C.D.;Duplessis, T.;Anderson, S.;Patel, E.;Bachstetter, A.;Van Eldik, L.J.;Nelson, P.T. "Hippocampal Sclerosis of Aging Can Be Segmental: Two Cases and Review of the Literature." Journal of neuropathology and experimental neurology 74, 7 (2015): 642-52.
- 5. Nelson, P.T.;Estus, S.;Abner, E.L.;Parikh, I.;Malik, M.;Neltner, J.H.;Ighodaro, E.;Wang, W.X.;Wilfred, B.R.;Wang, L.S.;Kukull, W.A.;Nandakumar, K.;Farman, M.L.;Poon, W.W.;Corrada, M.M.;Kawas, C.H.;Cribbs, D.H.;Bennett, D.A.;Schneider, J.A.;Larson, E.B.;Crane, P.K.;Valladares, O.;Schmitt, F.A.;Kryscio, R.J.;Jicha, G.A.;Smith, C.D.;Scheff, S.W.;Sonnen, J.A.;Haines, J.L.;Pericak-Vance, M.A.;Mayeux, R.;Farrer, L.A.;Van Eldik, L.J.;Horbinski, C.;Green, R.C.;Gearing, M.;Poon, L.W.;Kramer, P.L.;Woltjer, R.L.;Montine, T.J.;Partch, A.B.;Rajic, A.J.;Richmire, K.;Monsell, S.E.;Alzheimer’ Disease Genetic, C.;Schellenberg, G.D.;Fardo, D.W. "ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology." Acta neuropathologica 127, 6 (2014): 825-43.
- 6. Bowman, G.R.;Perez, A.M.;Ptacin, J.L.;Ighodaro, E.;Folta-Stogniew, E.;Comolli, L.R.;Shapiro, L. "Oligomerization and higher-order assembly contribute to sub-cellular localization of a bacterial scaffold." Molecular microbiology 90, 4 (2013): 776-95.
- UK NOW
Dr. Eseosa Ighodaro Leading the Way in the College of Medicine's MD/PhD Program
As a young student who was proficient in science, Dr. Eseosa Ighodaro, always saw herself pursuing a career in medicine. But it wasn’t until applying to medical school that she discovered there was another path she wanted to follow.
Dr. Fitzgerald Bramwell, former Vice President of Research and Graduate Studies and chemistry professor at the University of Kentucky, quickly recognized Dr. Ighodaro’s intelligence, persistence, and adaptability, which led him to suggest that she incorporate research into her studies as well. He later put her in contact with research-focused professors, including one professor at SUNY College, Dr. Robert M. Hoyte, who broadened Dr. Ighodaro’s research portfolio by giving her the opportunity to study in France.
“I found that I really loved both medicine and research,” Dr. Ighodaro said. “So when it came to deciding between medical school or graduate school, I found out about UK’s combined degree program, I applied, and got in. The rest is history.”
History, indeed. Dr. Ighodaro became the first African-American female graduate of the University of Kentucky College of Medicine’s MD/PhD program in 2019. It’s an accomplishment that she says took hard work, and one that she doesn’t take lightly. Even months after graduation, Dr. Ighodaro remains a bit speechless of her new platform to help empower future non-majority learners to pursue science-based careers.
“It’s an honor, and I’m extremely humbled,” she said. “I hope that we continue to encourage underrepresented students to follow this path because it can lead to rewarding, impactful careers.
“Diverse teams lead to improved research and health care delivery.”
Her main goal as a scientist and physician is to research health disparities and neurological disorders, shedding light on ensuring studies include all necessary variables to get the most accurate pictures of diseases and how they affect different populations. She was able to gather experience in these topics as a learner at UK, in 2017 serving as lead author of a paper published in the “Journal of Alzheimer’s Disease” that examined the challenges associated with studying dementia in African-American patients.
“During her tenure at UK, Dr. Ighodaro was able to transform institutional and social obstacles into stepping stones,” her mentor Dr. Bramwell said. “Of course, she had an outstanding academic record and an inquisitive mind. However, that has never been enough. Her achievement assumes even greater significance when one considers that such achievements by Black Americans in other areas of the country have a 30-year history.”
Dr. Ighodaro is currently in her first year of her neurology residency at Mayo Clinic in Rochester, Minn., during which she will work to become a board-certified neurologist before pursuing a fellowship to enhance her knowledge of strokes and dementia.
Her advice for those interested in earning a MD/PhD is to do some soul searching before committing to multiple years of medical education. “It’s a lifetime commitment,” she said. “Figure out your reasons for wanting to pursue medicine and research. And if you determine that you want to follow this path, get involved in various medical and research-oriented programs.”
She added that it’s also important to find a place where you’ll have a supportive group of students, learners, and faculty to encourage you along the way. Dr. Ighodaro says the support she received at UK was unmatched.
To be in a position where she can help patients from the bench to the bedside still feels a bit surreal for Dr. Ighodaro, but she can’t wait to begin her career and see her accomplishment pave the way for others who follow her lead.
“I think I’m still processing it all,” she said. “I’m very thrilled and feel so fortunate to earn such a degree. It’s definitely not an easy journey, but it’s worth it.”
For additional questions or information, you can email Dr. Ighodaro at firstname.lastname@example.org. To keep up-to-date with her medical and research practice, you can follow her on social media: Twitter (@Dr_Ighodaro) and FB (@Dr.Ighodaro).
Click here to watch a video about Dr. Ighodaro's accomplishments at UK.