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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg school of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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Early calcium dysregulation in Alzheimer's disease:setting the stage for synaptic dysfunction

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Science China(Life Sciences) 2011年第8期54卷 752-762页

作者： Shreaya CHAKROBORTY Grace E.STUTZMANN Department of Neuroscience Rosalind Franklin University/the Chicago Medical School

Alzheimer's disease(AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease *** plaques,neurofibrillary tangles and neuronal loss,though characteristic of AD,are late stage markers whose impact on the most devastating aspect of AD,namely memory loss and cognitive deficits,are still *** studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive *** common element that presents with several features of AD is disrupted neuronal calcium *** intracellular calcium levels are functionally linked to presenilin mutations,ApoE4 expression,amyloid plaques,tau tangles and synaptic *** this review,we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.

关键词： calcium Alzheimer's neuron synaptic dysfunction plasticity ER ryanodine CICR

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Chemical exposures and suspected impacton Gulf War Veterans

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Military medical Research 2023年第5期10卷 577-586页

作者： Rami Elhaj Joseph M.Reynolds Center for Cancer Biology Immunology and InfectionChicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA

Gulf War Illness(GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War(1990–1991). There are several hypothesized factors believed to contribute to GWI, including(but not limited to)exposures to chemical agents and a foreign environment(e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants,may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.

关键词： Gulf War Illness(GWI) Sarin Neuroinfammation Organophosphate(OP)

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Melanoma:Molecular genetics,metastasis,targeted therapies,immunotherapies,and therapeutic resistance

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Genes & Diseases 2022年第6期9卷 1608-1623页

作者： William Wagstaff Rimel N.Mwamba Karina Grullon Mikhayla Armstrong Piao Zhao Bryce Hendren-Santiago Kevin H.Qin Alexander J.Li Daniel A.Hu Andrew Youssef Russell R.Reid Hue H.Luu Le Shen Tong-Chuan He Rex C.Haydon The Pritzker school of Medicine and the Medical Scientist Training ProgramThe University of Chicago Medical CenterChicagoIL 60637USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Orthopaedic Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Surgery The University of Chicago Medical CenterChicagoIL 60637USA

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid *** some patients,early diagnosis and surgical removal of melanomas is lifesaving,while other patients typically turn to molecular targeted therapies and immunotherapies as treatment *** sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF,NRAS,and TERT genes,some of which can be therapeutically *** initially effective,many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory *** represent an alternative to molecular targeted ***,inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long *** the protocol for combination therapies develop,so will our scientific understanding of the many pathways at play in the progression of *** future direction of the field may be to find a molecule that connects all of the ***,noncoding RNAs have been shown to play important roles in melanoma development and *** noncoding RNAs may help us to understand how resistance e both primary and acquired e develops;ultimately allow us to harness the true potential of current *** review will cover the basic structure of the skin,the mutations and pathways responsible for transforming melanocytes into melanomas,the process by which melanomas metastasize,targeted therapeutics,and the potential that noncoding RNAs have as a prognostic and treatment tool.

关键词： BRAF inhibitors Checkpoint inhibitors Drug resistance Immunotherapy Melanoma Melanoma metastasis Skin cancer Targeted therapy Therapeutic resistance

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Esophageal resection for high-grade dysplasia and intramucosal carcinoma: When and how?

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World Journal of Gastroenterology 2010年第30期16卷 3786-3792页

作者： Vani JA Konda Mark K Ferguson Department of Medicine The University of Chicago Pritzker School of MedicineChicagoIL 60637United States Department of Surgery The University of Chicago Pritzker School of MedicineChicagoIL 60637United States

High-grade dysplasia (HGD) and intramucosal carcinoma (IMC) in the setting of Barrett’s esophagus have traditionally been treated with esophagectomy. However, with the advent of endoscopic mucosal resection and endoscopic ablative therapies, endoscopic therapy at centers with expertise is now an established treatment of Barrett’s-esophagus-related neoplasia, including HGD and IMC. Esophagectomy is today reserved for more selected cases with submucosal invasion, evidence for lymph node metastasis, or unsuccessful endoscopic therapy.

关键词： Barrett’s esophagus High-grade dysplasia Intramucosal carcinoma Endoscopic mucosal resection Esophagectomy

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Long noncoding RNA(lncRNA)H19:An essential developmental regulator with expanding roles in cancer,stem cell differentiation,and metabolic diseases

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Genes & Diseases 2023年第4期10卷 1351-1366页

作者： Junyi Liao Bowen Chen Zhenglin Zhu Chengcheng Du Shengqiang Gao Guozhi Zhao Piao Zhao Yonghui Wang Annie Wang Zander Schwartz Lily Song Jeffrey Hong William Wagstaff Rex CHaydon Hue HLuu Jiaming Fan Russell RReid Tong-Chuan He Lewis Shi Ning Hu Wei Huang Departments of Orthopedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Research Center Chongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China school of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA The medical Scientist Training Program The University of Chicago Pritzker School of MedicineChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene *** one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and ***,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or ***,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic *** discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of ***,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

关键词： Cancer Epigenetic regulation H19 LncRNA Long-noncoding RNA Metabolic diseases Stem cell differentiation

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Neural EGF-like protein 1(NELL-1):Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine

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Genes & Diseases 2017年第3期4卷 127-137页

作者： Mikhail Pakvasa Alex Alverdy Sami Mostafa Eric Wang Lucy Fu Alexander Li Leonardo Oliveira Aravind Athiviraham Michael J.Lee Jennifer Moriatis Wolf Tong-Chuan He Guillermo A.Ameer Russell R.Reid The University of chicago Pritzker School of MedicineChicagoIL 60637USA Laboratory of Craniofacial Biology and Development Section of Plastic and Reconstructive SurgeryDepartment of SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Rosalind Franklin University Chicago Medical SchoolNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Biomedical Engineering Northwestern UniversityEvanstonIL 60208USA Center for Advanced Regenerative Engineering Northwestern UniversityEvanstonIL 60208USA Department of Surgery Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611USA

Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant *** differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth *** EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive ***,it has been shown to repress adipogenic differentiation and ***-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of *** we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.

关键词： Bone tissue engineering Mesenchymal stem cells NELL-1 NEL-like protein 1 Osteogenic differentiation

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Lubiprostone vs Senna in postoperative orthopedic surgery patients with opioid-induced constipation:A double-blind,active-comparator trial

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World Journal of Gastroenterology 2014年第43期20卷 16323-16333页

作者： Christina M Marciniak Santiago Toledo Jungwhalia Lee Michael Jesselson Jillian Bateman Benjamin Grover Joy Tierny Department of Physical Medicine and Rehabilitation School of MedicineNorthwestern UniversityChicagoIL 60611United States Department of Preventive Medicine Feinberg School of MedicineNorthwestern UniversityChicagoIL 60611United States University of chicago medical Center ChicagoIL 60637United States The Rehabilitation Institute of chicago ChicagoIL 60611United States chicago College of Osteopathic Medicine ChicagoIL 60515United States

AIM: To investigate the efficacy of lubiprostone compared to Senna on bowel symptoms and constipation in post-operative orthopedic patients treated with opioids.

关键词： Constipation Opioids Lubiprostone Senna Orthopedics Rehabilitation

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T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein Ⅰ

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Cellular & Molecular Immunology 2019年第8期16卷 685-693页

作者： David Salem Rebecca Subang Masataka Kuwana Jerrold S.Levine Joyce Rauch Division of Rheumatology Department of MedicineResearch Institute of the McGill University Health CentreMontrealQCCanada Department of Allergy and Rheumatology Nippon Medical SchoolGraduate School of MedicineTokyoJapan Section of Nephrology Department of MedicineUniversity of Illinois at ChicagoChicagoILUSA Section of Nephrology Department of MedicineJesse Brown Veterans Affairs Medical CenterChicago IL USA

Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in *** to numerous molecularly distinct self-antigens emerge in a sequential manner over several years,leading to disease *** the earliest autoantibodies to appear are those targeting phospholipid-binding proteins,particularlyβ2-glycoprotein Ⅰ.Notably,mice immunized with β2-glycoprotein Ⅰ and lipopolysaccharide develop a strong T cell response to β2-glycoprotein Ⅰ that is associated with autoantibody production and renal disease,similar to that seen in human *** we hypothesized that mice with murine systemic lupus erythematosus,whether induced or spontaneous,should have T cells that recognizeβ2-glycoprotein *** evaluated the response of splenic T cells from mice with induced(C57BL/6 and C3H/HeN)and spontaneous(MRL/lpr)systemic lupus erythematosus to peptides spanning the entire sequence of humanβ*** found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope(peptide 31;LYRDTAVFECLPQHAMFG)in domain Ⅲ ofβ2-glycoprotein I.β2GPI-reactive CD4^(+)T cells from the two models differed primarily in cytokine production:T cells from mice with induced SLE expressed IFN-γ,while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ,indicating that IL-17-expressing T cells are not necessary for generating aβ2GPI-reactive T cell *** data suggest that the generation of aβ2-glycoprotein Ireactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.

关键词： β2-glycoprotein I T cells systemic lupus erythematosus autoantibodies MHC class II haplotypes

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz Jeffrey Hong Lily Song William Wagstaff Rex C.Haydon Hue H.Luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He Lewis L.Shi chicago medical school Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China school of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA Laboratory of Craniofacial Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and *** Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical *** of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling *** crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ ***-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic *** complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic ***,both stimulatory and inhibitory treatments come with potential risks that need to be *** review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt *** thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+*** description involved each of its components and their involvement in other cellular ***,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

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