Yi-Ping Li, PhD

Dr. Yi-Ping Li’s research, continuously sponsored by the NIH for 27 years’, covers a large scope of topics, including bone biology, musculoskeletal diseases, immune disorders, skeletal and craniofacial development, oral diseases, inflammatory diseases, tumorigenesis and cancer bone metastasis. These varied research interests have proven to be synergistic as there are overlapping themes and techniques. Dr. Li was one of the first scientists to apply molecular biology approaches to the study of osteoclasts. Dr. Li’s work resulted in the publication of a number of seminal papers on the cloning and characterization of the genes that are essential to osteoclast function or differentiation, including Cathepsin K, ATP6i, RGS10A, C/EBPα and Gα13. Dr. Li’s work has also resulted in the awarding of 6 patents. Dr. Li’s lab has a long history of experience using animal models to study the pathogenesis of human diseases. Dr. Yi-Ping Li has published many papers in high quality, peer-reviewed journals, such as Nature Genetics; Nature Communications; Genes & Development; PNAS; Journal of Cell Science; Development; Molecular and Cellular Biology; Journal of Immunology; Journal of Bone and Mineral Research; Molecular Endocrinology; Developmental Biology; Journal of Pathology; Human Molecular Genetics; Nucleic Acids Research and PLOS Genetics. 

Please see the detailed research projects at both https://medicine.tulane.edu/yi-ping-li-laboratories and Lab Webpage: https://www.yi-ping-li-lab.org

Current Research Interests

1. To characterize molecular mechanisms of tumorgenesis and cancer bone metastasis, and utilize immunotherapy to development new diagnostic and therapeutic alternatives to suppress cancer growth and metastasis. We have defined ATP6i as T cell activation regulator and Cathepsin K as dendritic cell maturation regulator and as a tumor suppressing gene and its role of mutation in prostate cancer metastasis. We have developed AAV mediated gene knockdown system for therapeutic alternatives for human breast cancer bone metastasis. We have also demonstrated that whole-body Ctsk knockdown or a small molecule inhibitor of Ctsk enhance the efficacy of immunotherapy by improving anti-tumor immunity and promoting dendritic cell maturation, and that osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity.
   
   Publications
   1. *Matthew McConnell, Shengmei Feng, Wei Chen, Guochun Zhu,  Dejun Shen,  Selvarangan Ponnazhagan,  Lianfu Deng,, and Li YP. Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget. 2017 May 2. PMID: 28504970;   PMCID: PMC5564597
   2. *Feng S, Guochun Zhu, Matthew McConnell, Lianfu Deng, Qiang Zhao, Mengrui Wu, Qi Zhou, Jinshen Wang, Jin Qi, Li Y-P,* and Wei Chen. Silencing of Atp6v1c1 Prevents Breast Cancer Growth and Bone Metastasis. International Journal of Biological Sciences 2013; 9(8): 853-862. PMCID: PMC3805834.
   3. Tu Q, Zhang J, Fix A, Brewer E, Li YP, Zhang ZY, Chen J. Targeted overexpression of BSP in osteoclasts promotes bone metastasis of breast cancer cells. J Cell Physiol 2008;218:135-45. PMCID: PMC2666312.

   4. Ping Z, Siegal GP, Harada S, Eltoum IE, Youssef M., Shen T, He J, Huang Y, Chen D, Li YP, Bland KI, Chang HR, Shen D. ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast. Oncotarget. 2016, 7(49), PMID: 27811364;  PMCID: PMC5340256.

       

2. To seek selectively shut off Immune responses and Specifically Activate immune responses.  AAV mediated gene therapy to prevent bone loss and inflammatory Diseases such as Rheumatoid arthritis (RA) and periodontitis, osteoarthritis (OA) and aging related diseases such as osteoarthritis (OA). We have applied my findings in osteoclast biology to translational medicine through a novel AAV mediated gene silencing tool targeting crucial osteoclast proteins (e.g. ATP6i, RGS10, C1, AC45 and Cathepsin K), which have the capacity to reduce bone loss and inflammation associated with oral diseases in mouse models of periodontal and endodontic diseases. My lab has investigated the therapeutic effect of AAV-sh-Apt6i, AAV-sh-Cathepsin K, and AAV-sh-RGS10. This groundbreaking work investigates the therapeutic potential of targeting ATP6i, RGS10, and Cathepsin K as treatments for immune-mediated oral inflammatory diseases and has led to numerous insights on the roles of these genes in osteoimmunology. Importantly, this work has shown that a number of critical osteoclast genes also have important roles in the immune system.
   
   Publications:
   1. *Hao L, Chen J, Zhu Z, Reddy MS, Mountz JD, Li Y-P*, Chen W. Odanacatib, Cathepsin K Specific Inhibitor, Inhibits Inflammation and Bone Loss Caused by Periodontal Diseases. J Periodontol. 2015 Apr 16:1-18. PMCID: PMC4648620
   2. *Liang Hao, Wei Chen, Matthew McConnell, Zheng Zhu, Sheng Li, Michael Reddy, Paul D. Eleazer4, Min Wang, Yi-Ping Li. A small molecule, Odanacatib, inhibits inflammation and bone loss caused by endodontic disease. Infection and Immunity. 2015, Apr;83(4):1235-45. PMCID: PMC4363442.
   3. *Zheng Zhu, Wei Chen, Liang Hao, Guochun Zhu, Yun Lu, Sheng Li, Lin Wang*, Yi-Ping Li*. Ac45 silencing mediated by    AAV-sh-Ac45-RNAi prevents both bone loss and inflammation caused by periodontitis. Journal of Clinical Periodontology. J Clin Periodontol. 2015 Jul;42(7):599-608. PMCID: PMC4620917.
   4. *Ma, J, Chen W, Zhang L, Tucker B, Zhu G, Sasaki H, Hao L, Wang L, Ci H, Jiang H, Stashenko P, and Li Y-P*. RNAi mediated silencing of Atp6i prevents both periapical bone erosion and periapical inflammation in the mouse model of endodontic disease. Infection and Immunity. 2013; 81 (4): 1021–1030. PMCID: PMC3639609.
3. To define the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in Rheumatoid arthritis and autoimmune diseases. The proposed study will provide important insights into the negative regulation of the cells of the immune system to target inflammation and bone destruction in RA by elucidating the underlying mechanism of Gα13 signaling. Knowledge gained from this study may generate potential therapeutic means for treating RA and other inflammatory bone diseases. We also characterizing the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions in mouse models. This study endeavors to understand how osteoclast (OC) differentiation is negatively regulated and to characterize the mechanism by which endogenous negative regulators of osteoclasts control bone homeostasis under physiological and pathological conditions.
   
   Publications:
   1. *Mengrui Wu, Wei Chen, Yun Lu, Guochun Zhu, Liang Hao and Li YP, Gα13 negatively controls osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signaling pathway. Nature Communications, 2017 Jan 19;8:13700, PMID: 28102206; PMCID: PMC5253683
   2. *Wu M, Wang Y, Deng LF, Chen W, Li Y-P. TRAF Family Member-Associated NF-κB Activator (TANK) Induced By RANKL Negatively Regulates Osteoclasts Survival and Function. Int J Biol Sci 2012; 8(10):1398-1407. PMCID: PMC3492797.
   3. *Wenbin Yang,  Zheng Zhu1, Longjiang Li,  Ning Gao, Abigail McVicar,  Lin Wang, Yi-Ping Li,  Wei Chen AAV-sh-Ac45 simultaneously inhibits bone resorption and attenuates inflammation through impairing acidification, Cathepsin K secretion, TLRs signaling activation, and the dendritic cell maturation pathway Infection and Immunity, 2020 Dec 15;89(1):e00436-20
   4. *Wang Y, Chen W, Hao L, McVicar A, Wu J, Gao N, Liu Y, and Li YP. C1 silencing attenuates inflammation and alveolar bone resorption in endodontic disease.  Journal of Endodontics 2019 Jul;45(7):898-906 
4. To characterize Znf9/CNBP as Myotonic dystrophy type II (DM2) disease gene and key regulators in craniofacial and skeletal development. Our research has had a major impact on the field of muscle disease and has expanded our understanding of the pathogenesis of DM2 disease. Prior to my findings, it was unknown that Znf9 haploinsufficiency was related to the pathogenesis of DM2 (Chen et al, JMB, 2007). I have also identified Cnbp for the first time as a key regulator in craniofacial development by using the mouse gene knockout system. My research has had a major impact on the field of craniofacial development, has expanded our understanding of the biological and molecular basis of craniofacial morphogenesis, and has provided much needed insights into human congenital birth defects which affect the development of the head, face, and neck. 
   
   Publications:
   1. *Chen W, Liang Y, Deng W, Shimizu K, Ashique AM, Li E, Li Y-P*. The zinc-finger protein, CNBP, is required for forebrain formation in the mouse. Development 2003; 130:1367-79. 
   2. *Abe Y#, Chen W#, Huang W, Li Y-P*. CNBP regulates forebrain formation at organogenesis stage in chick embryos. Dev Biol 2006; 295:116-27.
   3. *Chen W, Wang Y, Abe Y, Cheney L, Udd B, Li Y-P*. Haploinsuffciency for Znf9 in Znf9+/- mice is associated with multiorgan abnormalities resembling myotonic dystrophy. J Mol Biol 2007; 368(1):8-17. 
   4. *Shimizu K, Chen W, Ashique AM, Moroi R, Li Y-P*. Molecular cloning, developmental expression, promoter analysis and functional characterization of the mouse CNBP gene. Gene 2003; 307:51-62. 
5. To determine how osteoclasts resorb bone and which molecules are responsible to the bone resorption process. I am the major investigator who discovered the role of subunits of the osteoclast proton pump in osteoclast function at a time when the role of osteoclasts in bone resorption and mechanism of action of proton pumps was still largely unknown. We discovered that Cathepsin K is a major osteoclast-specific protease responsible for matrix protein degradation, that RGS10 transduces RANKL signaling to control osteoclast differentiation by regulating [Ca2+]i oscillation and activation of NFATc1. Furthermore, I made the novel discoveries that ATP6i (TCIRG1) is an osteoclast-specific subunit of the proton pump responsible for dissolving the mineral phase of bone. Based our work, ATP6i has been identified as a human osteopetrosis disease gene. These two molecules have been listed as major osteoclast function genes in the current model of osteoclast differentiation in the Principles of Bone Biology textbook (edited by Bilezikian JP et al., 2008).
   
   Publications:
   1. Li Y-P, Alexander M, Wucherpfennig AL, Yelick P, Chen W, Stashenko P. Cloning and complete coding sequence of a novel human cathepsin expressed in giant cells of osteoclastomas. J Bone Miner Res 1995;10:1197-1202.
   2. *Li Y-P, Chen W, Liang Y, Li E, Stashenko P. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 1999;23:447-51. 
   3. *Chen W, Yang S, Abe Y, Li M, Wang Y, Shao J, Li E, Li Y-P*. Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum Mol Genet 2007;16:410-23. PMCID: PMC3578583
   4. *Yang S, Chen W, Stashenko P, Li Y-P*. Specificity of RGS10A as a key component in the RANKL signaling mechanism for osteoclast differentiation. J Cell Sci 2007;120:3362-71. PMCID: PMC3587975.
6. To characterize mechanisms underlying how transcription factors and epigenetic factors regular osteoclast differentiation and activation. We have done novel works in investigating the mechanism underlying transcription factors specifying osteoclast lineage commitment from monocyte/macrophages and characterizing osteoclast genes and promoters. The studies have established C/EBPα as the key transcriptional regulator of osteoclast lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption (e.g. osteoporosis and arthritis) and leading the way for future exploratory studies. We have also demonstrated that C/EBPα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1. The function of osteoclast proteins makes them ideal targets for bone resorption related diseases, such as bone cancer metastasis, osteoporosis, periodontitis, and rheumatoid arthritis. Recently, we revealed that Gα13 is a master endogenous negative switch for osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signalling pathway.
   
   Publications:
   1. *Chen W, Zhu G, Hao L, Wu M, Ci HL, and Li Y-P*. C/EBPa is the Key Regulator of Osteoclast Lineage Commitment. Proc Natl Acad Sci U S A. PNAS. 2013; 110(18):7294-9. PMCID: PMC3645589.
   2. *Kamolmatyakul S, Chen W, Yang S, Abe Y, Moroi R, Ashique AM, Li Y-P*. IL-1α stimulates cathepsin K expression in osteoclasts via the tyrosine kinase-NF-κB pathway. J Dent Res 2004;83:791-6. PMCID: PMC3966556.
   3. *Mengrui Wu, Wei Chen, Yun Lu, Guochun Zhu, Liang Hao and Li YP*, Gα13 negatively controls osteoclastogenesis through regulation of the RhoA/Akt/GSK3β/NFATc1 signaling pathway. Nature Communications, 2017 Jan 19;8:13700, PMCID: PMC5253683.
   4. *Chen W, Zhu G, Tang J, Zhou HD, Li YP. C/ebpalpha controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1. J Pathol. 2018 Mar;244(3):271-282. doi: 10.1002/path.5001. PubMed PMID: 29083488.
7. To characterize the function of transcription factors and epigenetic factors in bone and revealed its crucial roles in the development of osteoblasts, bone and cartilage. My lab has recently published several papers exploring the underlying mechanism by which Cbfβ, a key binding factor for Runx proteins, regulates cartilage and bone development. We have investigated the pathogenesis of cleidocranial dysplasia (CCD) and revealed that CCD may result from functional defects of the Runx2/Cbfβ heterodimeric complex in various skeletal cells. Cbfβ has been found to play an indispensable role in postnatal skeletal development and homeostasis in various skeletal cell types by up-regulating the expression of Atf4 and Osterix. We have  characterized the mechanism by which Cbfβ regulates chondrogenesis and osteoblastogenesis and revealed that Cbfβ controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog expression and inhibiting parathyroid hormone-related protein receptor expression in postnatal cartilage and bone formation. 
   
   Publications:
   1. *Tian F, Wu M, Deng L, Zhu G, Ma J, Gao B, Wang L, Li YP*, Chen W*. Core binding factor beta (Cbfb) controls the balance of chondrocyte proliferation and differentiation by up-regulating Indian hedgehog (Ihh) expression... J Bone Miner Res. 2014 Jul;29 (7):1564-74. PMID: 24821091. PMCID: PMC4644666 
   2. *Wu M, Li YP, Zhu G, Lu Y, Wang Y, Jules J, McConnell M, Serra R, Shao JZ, Chen W*. Chondrocyte-specific knockout of Cbfβ reveals the indispensable function of Cbfβ in chondrocyte maturation, growth plate development and trabecular bone formation in mice. Int J Biol Sci. 2014 Jul 29;10(8):861-72.  PMID: 25170300, PMCID: PMC4147220
   3. *Wu M, Li C, Zhu G, Wang Y, Jules J, Lu Y, McConnell M, Wang YJ, Shao JZ, Li YP*, Chen W*. Deletion of core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development. Bone. 2014 Aug; 65:49-59. PMID: 24798493, PMCID: PMC4644668
   4. *Chen W, Ma J, Zhu G, Jules J, Wu M, McConnell M, Zhou X, Tain F,  Paulson C, Wang L, and Li YP*. Cbfb Deletion in Mice Recapitulates Cleidocranial Dysplasia and Reveals Multiple Functions of Cbfb; Required for Skeletal Development. Proc Natl Acad Sci U S A. (PNAS). 2014; 111(23): 8482-7. PMID: 24850862, PMCID: PMC4060659

*Indicates that the PI (Dr. Yi-Ping Li) is the correspondence author

RESEARCH FUNDING

Grant Name                     R01 AR074954

Role in Project:                  Principal Investigator
Year (Inclusive):                02/15/20-02/14/25
Source:                              NIH;NIAMS

Grant Name                      R01 DE023813

Role in Project:                  Principal Investigator
Year (Inclusive):                03/20/19-04/30/24
Source:                             NIH; NIDCR

Grant Name                     R01 DE028264

Role in Project:                  Principal Investigator
Year (Inclusive):                09/01/18 - 08/31/23
Source:                             NIH; NIDCR

Grant Name                     R01 AR075735

Role in Project:                  Principal Investigator
Year (Inclusive):                08/01/19 - 07/31/24
Source:                             NIH; NIAMS