Shirley ShiDu Yan

School of Pharmacy - Pharmacology & Toxicology, Pharmacy Administration
Howard E. Mossberg Distinguished Professor
Primary office:
785-864-3637
Smissman Research Laboratories
Room 164
University of Kansas
2099 Constant Avenue
Lawrence, KS 66047-2535


Expertise and Current Research Activity

Yan’s research focuses on investigating the cellular and molecular mechanisms underlying neuronal stress and survival in neurodegenerative disorders including Alzheimer’s disease (AD). AD is the sixth leading cause of all deaths in the United States and is the fifth leading cause of death in Americans aged ≥65 years.

Although other major causes of death have been on the decrease, deaths because of AD have been rising dramatically. There are an estimated 36 million all over the world and 5.4 million cases in US. Each day on average, 1,252 people are diagnosed with AD. AD now afflicts one in eight Americans over the age of 65 and some 47 percentage of Americans over the age of 85 (Alzheimer Association). Unfortunately, there are very limited drug targets for the treatment of AD currently. Thus, it is urgent to explore and develop new therapeutic approaches for halting and treating AD.

Recent studies highlight that mitochondrial dysfunction is an early pathological feature of AD. Inhibiting amyloid beta peptide (Aβ)-induced mitochondrial toxicity is a promising and novel approach to improving cognitive function and preventing and/or slowing the progression of AD. Amyloid binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme, is one such promising therapeutic target to achieve Aβ inhibition. ABAD interacts with Aβ to facilitate neuronal and cognitive dysfunction in AD. Studies showed that antagonizing Aβ-ABAD interaction significantly reduces Aβ accumulation, protects against aberrant mitochondrial and neuronal function, and improves learning and memory in AD transgenic mice. We have designed and synthesize a family of novel small molecule inhibitors for blocking Aβ-ABAD interaction and improving mitochondrial and neuronal function. These small molecule ABAD inhibitors hold a great potential for therapeutic strategy for AD, which will greatly benefit to millions of AD suffers. These studies have been published in Chem Biol Drug Des 2013, 81, 238-49 and just accepted by Current Alzheimer Research for the publication in 2014. University of Kansas has patented small molecule ABAd inhibitors (Pub. N0.2 US 2010/0204183 A1).

Education

M.S., Histopathology, Fujian Medical College

M.D., Medicine, Fujian Medical College

Research

Dr. Yan’s research focuses on investigating the cellular and molecular mechanisms of cellular stress and survival in neurodegenerative disorders relevant to Alzheimer’s disease (AD) and Parkinson disease. She has first identified the specific cellular targets (RAGE, receptor for advanced glycation end product; and ABAD, amyloid binding alcohol dehydrogenase) of amyloid-beta peptide (Aβ) and found the evidence of Aβ-mediated neuronal stress. She developed a novel transgenic mouse model relevant to AD and tested the role of RAGE and ABAD in Aβ-mediated cellular perturbation in those AD type mouse models. She was the first to describe the RAGE and ABAD as the functional binding proteins for Aβ. Dr. Yan and her research team are the major group investigating these paradigms. Dr. Yan and her research team have provided evidence that cell surface molecule (RAGE) and mitochondrial enzyme (ABAD) serve as cofactors for promoting and exaggerating neuronal and mitochondrial toxicity in an Aβ-rich environment.

Mitochondrial dysfunction is a hallmark of AD. Dr. Yan and her research team have followed up their studies and first found that Aβ progressively accumulated in mitochondria of brains from AD patients and transgenic AD-type mouse model. Accumulation of Aβ in mitochondria was associated with mitochondrial dysfunction. ABAD directly linked to mitochondrial toxicity induced by Aβ. These studies provide new insights into mechanisms of Aβ-mediated mitochondrial toxicity causing neuronal damage relevant to AD and open new avenue for treatment of AD. Recently, Dr. Yan’s group have provided substantial evidence of mitochondrial abnormalities directly link to the synaptic dysfunction which is an early feature in the AD pathogenesis. These studies open new avenue for therapeutic strategy of AD. As stated by the committee of my NIH grant review, Dr. Yan is a pioneer in the studies RAGE/ABAD and their roles in an Aβ-induced mitochondrial and neuronal perturbation of AD. She is a highly regarded and world-wide leader in the field of AD neuropathogenesis and has made very important contributions to the AD field. Her research projects are very innovative. Dr. Yan and her research team are the major group investigating these paradigms (RAGE/ABAD, mitochondria and pathogenesis of AD).

These studies have been highlighted in world-wide leading Journals including Nature (2 papers), Nature Medicine (10 papers), Science, PNAS, and other professional leading Journals. The paper on CypD (Du et al., Nature Medicine, 2008) was ranking top#3 of hot papers in Alzheimer's disease research in year 2008-2010 (http://www.timeshighereducation.co.uk/story.asp?sectioncode=26&storycode...). She is a keynote speaker at multiple international professional scientific meetings and member of scientific review committee. Her research projects are continuously supported by NIH. She has received grant award from NIA [Program Project Grant since 2000, a total of $14 million for 10 years period (07/01/2000-06/30/2012)] to continually support her research on aging and Alzheimer’s disease. Her work clearly advances our understanding of mechanisms through which Aβ induces cellular stress and moves AD field forward. Her work could lead to new therapeutic strategies for AD. In addition, results generated from our studies have been patented or filed for the patent applications. RAGE antagonists are in the clinical trial (phase II). Based on her exceptional outstanding research and track record of publication, she has recently received extraordinary MERIT (Method to Extend Research in Time) award (R37) from NIA. MERIT award is one of the most prestigious awards presented by the NIH and provide long-term support to exceptional outstanding and experienced investigators who contributes significantly to the research field. MERIT awards enable scientists who have impressive track records of scholarship and productivity to have long-term sustained funding without the time and effort of seeking competitive grant renewal.

Research conducted in my laboratory is geared toward unraveling the cellular and molecular basis of neurodegeneration and devising therapeutic strategies to hamper the processes that cause neuronal death. To this end, we have focused our research efforts on the transgenic animal model of Alzheimer’s disease. We have developed a novel transgenic mouse model relevant to the pathogenesis of AD, such as transgenic mice expressing both mutant form of human APP and RAGE or ABAD targeted to neurons, smooth muscle cells, endothelial cells, respectively, and deletion of ABAD gene. Those novel transgenic AD-type mouse models greatly benefit the scientific AD communities. Some of these transgenic mouse models have been listed in the Double-cross research models of Alzheimer Research Forum (http://www.alzforum.org/res/com/tra/double-cross/default.asp).Through analyses of genetically manipulated AD-type mouse models, we have elucidated new insight into cellular and molecular mechanisms underlying the pathogenesis of AD.

Dr. Yan also has an expertise on cellular and molecular mechanisms of ischemia-induced cardiac and cerebral injury, autoimmune disease such as EAE (experimental autoimmune encephalomyelitis) animal model relevant to multiple sclerosis, and Parkinson’s disease. Those studies are supported by NIH and other foundation grants.

I have received the Zenith Fellow Award from the Alzheimer’s Association in 2005. The Zenith Fellow Award only gives an established independent investigator who has contributed significantly to the field of Alzheimer’s disease research. I am an active member of multiple scientific review committees for neurodegenerative disease of National Institute of Health (NIH), VA merit grant, and other foundation grants.

Her Laboratory has been collaborating with research scientists from Japan, Germany, Italy, Saudi Arabia, and United Kingdom, in addition to United States.


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