Regulation of Bone Mass in Alzheimer’s disease
- Research in the C. Crish Lab centers on neurodegenerative mechanisms of osteoporosis in Alzheimer’s disease (AD). We are focused on identifying how central mechanisms that regulate bone growth may be affected by AD pathology, and how estrogen is synthesized in the brain may provide protective effects against both osteoporosis and AD.
- Osteoporosis occurs in patients with AD at higher rates than in age and mobility-matched counterpart – amplifying health care complexities, disability and mortality.The relationship between these disorders may relate to a common mechanism where decreased bone mass is an early symptom of a neurodegenerative process.
- Our lab is interested in determining how bone mineral density changes over time in a variety of Alzheimer’s mouse models that represent different pathological mechanisms of the disease.Our goal is to determine the temporal relationship between AD pathology and skeletal phenotype and if brain areas that regulate bone in these mice are damaged early in the progression of the disease. Additionally, we are interested in investigating the mechanisms by which AD disrupts central signaling that regulates bone mass.
Shared Neurodegenerative Mechanisms in Glaucoma and AD
- Glaucoma is the leading cause of irreversible blindness worldwide, and over the past decade, our perspective on glaucoma has shifted from considering it solely an eye disease to identifying it as an age-related degenerative disorder of the central nervous system.
- Mounting evidence suggests that glaucoma shares a number of epidemiological and mechanistic similarities with other age related neurodegenerations such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease. Therefore, mechanisms that play a role in the onset or progression of pathology in those diseases may also be relevant in glaucoma.
Research in the Crish Lab is concerned with pre-apoptotic changes occurring in glaucoma. Recently, as in other age-related neurodegenerative disorders, there have been a number of studies suggesting that functional deficits and compartmentalized degeneration occur well before cell death in glaucoma. It is unclear how much these pathologies produce the clinical symptoms characteristic to this disease or how they relate to eventual cell body loss.
We are most interested in exploring how defects in axonal transport, metabolism, and physiology:
- drive axonal and somatic degeneration;
- correlate to loss of function; and
- represent targets for interventions to improve outcome.
This research will serve to better define glaucoma’s progression and allow the development of more effective treatments.
Additionally, the Crish Lab studies naked mole-rats which are naturally blind fossorial rodents endemic to eastern Africa. We’re interested in evolutionary and developmentally degenerated visual systems and naked mole-rats are excellent for this research pursuit. And naked mole-rats are just plain interesting—we are also pursuing studies on their somatosensory system, social organization, reproduction and skeletal growth!
Our research primarily focuses on the development of neuroprotective and therapeutic strategies for the treatment of neurodegenerative diseases and psychiatric disorders. The research program is involved in elucidation of the oxidative stress, inflammation and energy dysregulation in the pathogenesis of neurological illnesses and investigating the therapeutic potential of antioxidants and anti-inflammatory as well as bioenergy substrates in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease as well as psychiatric illnesses such as schizophrenia and post traumatic disorder. Of particular interest is the investigation of the pharmacological properties of natural products such as dietary polyphenols (resveratrol, curcumin and tea catechins and theaflavins). Additionally, we are interested in the elucidation of the neurochemical mechanisms involved in the neurotoxicity of amphetamines.
We also investigate the mechanism of action and receptor pharmacology of both typical, atypical and novel antipsychotic drugs. Of particular interest is the contribution of both dopaminergic and serotonergic receptors to the neurochemical effects and therapeutic potential of antipsychotic agents.
Preclinical studies utilize techniques such as in vivo microdialysis, HPLC, biochemical assays of neuronal metabolites and biomarkers as well as western blotting and northern blotting techniques.
The Fleming lab conducts basic and translational research on Parkinson’s disease (PD), the common neurodegenerative movement disorder. Parkinson’s disease is part of a group of neurodegenerative disorders characterized by the abnormal accumulation of the presynaptic protein alpha-synuclein in lewy bodies and lewy neurites called synucleinopathies. We make use of tools and methods supplied by genetics, molecular biology, and behavioral neuroscience, all in an effort to identify mechanisms underlying abnormal protein accumulation and neurodegeneration in synucleinopathies. In the laboratory we test potential neuroprotective therapies using multiple models of PD. Here, we employ a battery of motor and non-motor behavioral assays to determine therapeutic efficacy and in the brain we measure PD-related pathology including alpha-synuclein aggregation, autophagy, inflammation, and mitochondrial efficiency. In addition to preclinical research we also study gene-gene and gene-environment interactions related to alpha-synuclein pathology.
Pharmacokinetics and toxic reaction of new generation synthetic cannabinoids
Marijuana, or Cannabis sativa, is one of the most pervasive drugs in the world due to its popularity in both medicinal and recreational use with a significant increase in consumption being reported in the United States during the 21st century. Synthetic cannabinoids (SCBs) are substances designed to mimic the main psychoactive ingredient in marijuana, Δ9-tetrahydrocannabinol (THC). While researchers study the therapeutic potential of SCBs, the use of SCBs has deviated from its original intent, leading to abuse by the general public due to their low cost, ease of availability, and difficulty of detection. SCBs are marketed as being natural and safe to consumers; however, they are neither natural nor safe, causing serious adverse reactions, including seizures, nephrotoxicity, and in some cases, death. With their growing popularity, the number of cases reporting adverse reactions to SCBs is increasing. Currently, the mechanisms of SCB-induced tissue toxicity are unknown, and emergency therapy to detoxify accumulated SCBs in intoxicated users does not exist. As opposed to FDA-approved drugs, the disposition and metabolism properties of SCBs NPSs are unknown. Dr. Fujiwara put his effort into characterizing the pharmacokinetics and toxic reaction of new generation SCBs.
Our research is focused on the translational aspects of the intermediary metabolism. In particular, we are interested in the pathophysiology of nonalcoholic fatty liver diseases (NAFLD), type 2 diabetes mellitus (T2DM) and their cardiovascular disease (CVD) related complications. We investigate insulin resistance, inflammation and oxidative stress-induced hepatic and cardiac mitochondrial dysfunctions, and abnormalities in the intermediary metabolism. We also study the role of metabolic syndrome in impaired lipoprotein biogenesis, remodeling and lipid transport implicated in atherosclerosis. We employ wide-range in vitro (isolated and reconstituted lipoproteins, cells and mitochondria) and in vivo (animal and human studies) models to explore these questions. Our projects heavily rely on the utilization of high resolution mass spectrometry-assisted metabolomics, and proteomics techniques coupled with the stable isotope-based flux studies.
Our current research projects include:
- Regulation of the high density lipoprotein (HDL) metabolism in T2DM.
- Investigation of the link between hepatic inflammation and atherosclerosis in NAFLD.
- Exploration of the role of oxidative stress in hepatic mitochondrial dysfunction in NAFLD.
- The effect of aging on cardiac mitochondrial dysfunction.
Metabolomics and Proteomics
We use targeted metabolomics to study alterations in the citric acid cycle, anaplerosis/cataplerosis, amino acid, fatty acid and sphingolipid metabolism. Our stable isotope-based flux studies investigate the temporal changes in metabolites and provide information on the activities of metabolic pathways.
We also apply static and dynamic proteomics approaches to investigate stability and turnover rates of proteins, and protein-protein interactions in health and diseases.
Our clinical studies are conducted in collaboration with Drs. McCullough, Dasarathy and Kashyap from CCF. We are also collaborating with Dr. Hoppel from CWRU to study cardiac mitochondrial dysfunction in aging heart and Dr. Sadygov from UTMB to develop bioinformatics tools to facilitate these studies.
Research interests include the design, development and application of novel nanoparticulate/microparticulate delivery systems, the assessment of novel drug delivery systems using in-vitro and in-vivo models, targeted drug delivery systems in cancer, neuroprotection and neurodegeneration, nasal drug delivery systems in CNS diseases, and oral delivery of macromolecules.
The overarching research theme of the lab is to elucidate the early biological changes underpinning Alzheimer’s disease, revealing avenues for new, effective therapeutic strategies to combat this devastating disease.
One project seeks to identify how the immune system contributes to sex differences in Alzheimer’s disease incidence and progression.
Another line of research seeks to understand how microglia, the resident immune cells of the brain, interact with other immune cell populations to initiate and perpetuate Alzheimer’s disease processes.
My laboratory is primarily interested in drug design and discovery, protein structure/function, computational chemical biology, and bioinformatics.
Recently, we have successfully established the motif-guided drug screening pipeline by using a computer-aided drug design (CADD) approach. By the application of computational pipeline, we focus on the development and optimization of well-balanced interdisciplinary methods from in silico model to the experimental approach targeting antibacterial, antiviral, anticancer, and neurological disorder therapies.
i) Our lab seeks to discover new chemical reagents and therapeutic leads that can illuminate biological problems. Our precise drug discovery research focuses on the clarification of specific protein-ligand and protein-protein interactions involved in the discovery of potent drug candidate and drug delivery system using state-of-the-art CADD techniques. Also, we develop a consistent molecular and cell-based model to correlate the observed structure-activity relationship (SAR) study with X-ray crystallography, confocal microscopy, genomics, proteomics, flow cytometry, and in vivo studies. The final goal of research interest is to design and develop concurrent combinational therapies that take into account structural precise mechanisms of certain diseases and pharmacokinetics.
ii) For a long-term strategy, we also are heavily involved in the development of molecular pattern recognition algorithm to uncover the foundation of drug resistance. Developing the automatic computational mutant pattern recognition algorithm can effectively assess the structural and sequential correlations of mutational evolution of proteins, which is a currently missing link in the understanding of the disease. This finding of the foundational pattern can be used to predict and release the future outbreak and way to design the optimized combinatory therapy for clinical use.
Assistant Professor of Pharmaceutical Sciences
Associate Director, Integrated Pharmaceutical Medicine (IPM) Graduate Program
My research focus is to understand the neurobiological mechanisms that disrupt eye-brain communication in injury and disease. Using blend of classic neuroanatomical and neurophysiological techniques and new/innovative high-resolution correlative microscopy approaches (epifluorescent, electron, and multiphoton), my lab can identify and assess structural and functional changes occurring to injured/diseased neurons .
Long-term we are interested in improving diagnostic capabilities through developing approaches that take advantage of the relative accessibility of the eye to isolate and track neuron dysfunction occurring in the brain. Currently we are exploring the role of a subset of retinal neurons, ipRGCs, in adolescent traumatic brain injury (TBI). We posit that pre-degenerative alternations to these specific, unique, and vulnerable neurons are likely responsible in part for the visual and vision-influenced symptoms commonly experienced by patients after brain trauma.
Interindividual variability in drug response is a major challenge in drug therapy. Over the past years, precision medicine has received growing interest. However, our knowledge about the variability in drug response remains limited.
Dr. Wang’s lab focuses on identifying genetic and non-genetic factors that contribute to interindividual variability in drug metabolism and disposition using multiple omics in both basic and clinical settings. Combining pharmacokinetics, pharmacogenomics, proteomics, and metabolomics approaches, we aim to improve the understanding of the variations of drug-metabolizing enzymes and transporters, and the associated interindividual variability in the disposition and therapeutic outcomes of various medications. We expect to improve the efficacy and safety of drugs by identifying biomarkers that can predict individual drug responses and translating these findings into clinical precision pharmacotherapy.
Adjunct Professor of Pharmaceutical Sciences
Director, Translational Research Center
Abnormal synaptic changes contribute to the majority of neurological diseases.
Focusing on the auditory system, Dr. Bao’s research group has been studying whether two ‘opposite disorders’, hearing loss and tinnitus, are both the result of abnormal synaptic changes that occur due to aging or early noise exposure. This group has been working to understand basic cellular and molecular mechanisms underlying these abnormal changes, employing a variety of molecular, behavioral, electrophysiological, and imaging methods. At the same time, the group has also explored translational opportunities to treat these disorders with pharmacogenomic approaches and stem cell therapies. Recently, the group discovered an effective means for eliminating or delaying hearing loss with drugs that are already approved by the U.S. Food and Drug Administration (FDA) for other indications. With funding from both the National Institutes of Health (NIH) and other sources, the group continues to explore basic mechanisms underlying these age-related disorders and other sources, the group continues to explore basic mechanisms underlying these age-related disorders and simultaneously develop both drug and stem cell therapies to treat these common diseases.
Based on recent seminal preclinical studies from Dr. Bao’s research group showing that antiepileptic drugs that block calcium channels effectively diminish presbycusis, a collaborative research project has been established to test whether the severity of age-related hearing loss is correlated with specific genetic variants in genes encoded for calcium signaling as well as whether causal genetic variants in the same genes associated with better hearing can be determined in elderly persons taking calcium channel blockers. The long-term goal of this project is to develop a personalized medical intervention for presbycusis. The innovative aspect of this study is to apply pharmacogenetic approaches to discover personalized medications to prevent presbycusis.
In addition to Dr. Bao’s research group, a multidisciplinary team has been assembled that includes: Dr. Zhenyu Jia and Mike Hewit of NEOMED; Drs. Cliff Megerian, Gail Murray, and Qing Yin Zheng from Case Western Reserve University School of Medicine; and Drs. Nancy Tye-Murray and Jay F. Piccirillo from Washington University School of Medicine. This project represents a unique opportunity that brings together a diverse team for the purpose of conducting translation research to improve health outcomes of patients at risk for presbycusis.
Regulation of bone cell development and function, with specific emphasis on growth factors that can enhance osteogenesis
Bone loss is a major health care problem in the United States and worldwide. Risk factors associated with osteoporosis, include estrogen-deficiency (post-menopuasal) and aging. During bone development and its maintenance, the antagonistic processes of bone formation and resorption are regulated by various systemic and local factors (hormones, growth factors, cytokines, etc). It is evident that bone formation during skeletal modeling/remodeling and fracture repair requires stringent control of osteoblast proliferation and differentiation. Regulation of these biological processes involves sequential expression of cell growth and tissue specific genes in response to different regulatory signals.
Dr. Safadi’s research laboratory focuses on the regulation of bone cell development and function, with specific emphasis on growth factors that can enhance osteogenesis. We are interested in various metabolic bone diseases such as age/estrogen-induced osteopenia, osteopetrosis and cartilage-associated diseases (osteoarthritis and rheumatoid arthritis). The goal of our research is understand the pathological mechanisms underlying various bone diseases in order to develop strategies for the therapeutic management of such diseases. We identified a novel growth factor (named Osteoactivin) that has anabolic effects on bone. If we understand the mechanisms responsible for this effect, then this factor could be used as potential therapeutic agent to stimulate bone formation in diseases associated with osteopenia, increased risk of fracture and spinal fusion.
In addition, we developed an interest on the role of osteoactivin (gpnmb) as a neuroprotective factor for neurodegenerative diseases such as Parkinson’s disease and Alzheimer disease. This research is conducted in collaboration with the neurodegenerative research group at NEOMED. We also interested on the role of gpnmb as anti-inflammatory factor in acute and chronic conditions for wound healing and neuroinflammation.
Dr. Safadi’s laboratory is also working on another collaborative research with Dr. Mary Barbe at Temple University School of Medicine. Dr. Barbe laboratory utilizes an in vivo model for cumulative trauma disorder that focuses on the molecular and cellular mechanisms associated with tendonitis and inflammation-induced bone loss.
Research in Dr. Zhang’s group aims to understand how bile acid, lipid and glucose metabolism is regulated under physiological and pathological conditions. Dysregulation of bile acid, lipid and/or glucose metabolism may contribute to the pathogenesis of fatty liver disease, diabetes, obesity and atherosclerosis. Dr. Zhang’s group is working on different metabolic targets, including nuclear hormone receptors (FXR, HNF4a, RARa), carboxylesterases, microRNAs, long non-coding RNAs, etc. These targets may play a role in the pathogenesis of metabolic disorders or may serve as therapeutic target(s) for treatment of the common metabolic diseases.
Recent representative publications from Dr. Zhang’s group:
1. Xu, J, Li Y, Chen, W-D., Xu, Y., Yin, L., Ge, X., Jadhav, K., Adorini, L. and Zhang, Y. 2014. Hepatic Carboxylesterase 1 is essential for maintaining normal and farnesoid X receptor-mediated lipid homeostasis. Hepatology, 59(5):1761-71. PMID: 24038130. PMCID: 547667
2. Xu, Y., Zalzala, M., Xu, J., Li, Y., Yin, L., and Zhang, Y. 2015. A Metabolic Stress-inducible miR-34a-HNF4 Pathway Regulates Lipid and Lipoprotein Metabolism. Nature Communications, 6:7466. doi: 10.1038/ncomms8466. PMID: 26100857. PMCID: PMC4479415
3. Li, Y., Zalzala, M., Jadhav, K., Xu, Y., Kasumov, T., Yin, L., and Zhang, Y. 2016. Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, ER stress and lipogenesis and is regulated by HNF4alpha. Hepatology. 63(6):1860-74. PMID: 26806650. PMCID: PMC4874867
4. Xu, Y., Xu, J., Zalzala, M., Jadhav, K., Adrini, L., Lee, Y.K., Yin, L., and Zhang, Y. 2016. FXR Activation Increases Reverse Cholesterol Transport by Modulating Bile Acid Composition and Cholesterol absorption. Hepatology. 64(4):1072-85. PMID: 27359351, NIHMSID: 799688
5. Xu J., Xu Y., Xu Y., Yin L., Zhang Y., 2017. Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr~/~mice. Scientific Reports. 19;7(1): 17845. PMID: 29259301
6. Jadhav, K., Xu, Y., Xu., Y., Li, Y., Xu, J., Xu, Y., Adroni, L., Lee, Y.K., Yin, L., and Zhang, Y. 2018. Reversal Metabolic Disorders by Activation of the Bile Acid Receptors FXR and TGR5. Molecular Metabolism, pii: S2212-8778 (17) 30919-5. PMID: 29361497