About

Sihong Song, Ph.D., is a Professor in the Department of Pharmaceutics at the University of Florida College of Pharmacy. His research interests include the molecular and cell biology of gene expression and regulation, with a focus on liver and muscle gene delivery, gene therapy for diseases such as type 1 diabetes and alpha 1 antitrypsin deficiency, and adeno-associated virus (AAV) vector biology, including DNA persistence, integration, and interaction with cellular factors. He is engaged in developing gene therapy approaches for common diseases using recombinant Adeno-Associated Virus (rAAV) vectors mediated gene transfer. Dr. Song's work aims to improve the safety and efficiency of rAAV vectors by understanding the molecular mechanisms of their persistence and integration in mammalian cells. His research also explores host immune responses to transgene products. He has been involved in various funded projects, including the development of gene therapies for inflammatory bowel diseases, lupus, and osteoporosis, as well as studies on the circadian clock protein BMAL and its regulation of ENaC in the kidney. Dr. Song holds a Ph.D. and postdoctoral experience from the University of Florida and has contributed significantly to the field of gene therapy and vector biology.

Research topics

• Biology
• Chemistry
• Cell biology
• Medicine
• Materials science
• Chemical engineering
• Thermodynamics
• Internal medicine
• Endocrinology
• Computational biology
• Organic chemistry
• Biochemistry
• Physical chemistry

Selected publications

• Alpha 1 Antitrypsin Suppresses Autoantibody Production and Cellular Autoimmunity in Chronic Graft-Versus-Host Disease (cGVHD) in a Lupus Mouse Model

  Biomolecules · 2026-03-01

  articleOpen accessSenior authorCorresponding

  Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE.

  PublisherOA PDFDOI

• Functional Evaluation of Computationally Designed IL-10 in IL-10 KO Mice

  Biomolecules · 2026-03-23

  articleOpen accessSenior author

  Studies have shown that IL-10 has therapeutic potential for inflammatory diseases. However, it is challenging to use IL-10 as a therapeutic drug because it also possesses pro-inflammatory functions. To reduce these pro-inflammatory effects of IL-10, we have designed three IL-10 mutants using structure-based computational design technology. We demonstrated that these mutants exhibited significantly lower activity in IL-10-responsive cell lines than wild-type IL-10. Using recombinant adeno-associated virus (rAAV8) vectors expressing wild-type or mutant IL-10 molecules, we performed gene therapy experiments in IL-10 KO mice. The results showed that our vectors mediated high levels of transgene expression. Importantly, IL-10 gene therapy increased body weight gain, reduced colon injury, and prevented the development of inflammatory bowel disease (IBD). Moreover, IL-10 mutant gene therapy elicited significantly lower stimulation of CD8 T and NK cells compared with the wild-type IL-10 group. In summary, our IL-10 mutants provide a protective effect comparable to wild-type IL-10 in the IL-10 KO mouse model, suggesting that they may potentially have reduced pro-inflammatory function. While rigorous investigations of safety and efficacy in different disease models will be required, these results indicate the therapeutic potential of IL-10 mutant gene therapy for inflammatory diseases such as IBD.

  PublisherOA PDFDOI

• Administration of Purified Alpha-1 Antitrypsin in Salt-Loaded Hypertensive 129Sv Mice Attenuates the Expression of Inflammatory Associated Proteins in the Kidney

  Biomolecules · 2025-06-30 · 1 citations

  articleOpen access

  BACKGROUND: Alpha-1 antitrypsin (AAT) is a multifunctional protease inhibitor that has been shown to have anti-inflammatory properties in various diseases. AAT has been reported to protect against renal injury via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. However, its role in mitigating renal inflammation and reducing high blood pressure induced by salt-loading has never been studied. METHODS: In this study, we salt-loaded 129Sv mice to induce hypertension and then administered purified human AAT (hAAT) or the vehicle to investigate whether renal inflammation and associated inflammatory/signaling pathways are mitigated. RESULTS: Western blotting and densitometric analysis showed administration of hAAT attenuated protein expression of kidney injury molecule-1 (KIM1), CD93, CD36, and the toll-like receptor 2 and 4 (TLR-2/4) in kidney lysates. Similarly, protein expression of two key inflammatory transcription factors, signal transducer and activator of transcription 3 (STAT3) and NF-Kappa B were shown to be attenuated in the kidneys of 129Sv mice that received hAAT. Conversely, hAAT treatment upregulated the expression of heat shock protein 70 (HSP70) and immunohistochemistry confirmed these findings. CONCLUSIONS: Purified hAAT administration may be efficacious in mitigating renal inflammation associated with the development of hypertension from salt-loading, potentially through a mechanism involving the reduction of pro-inflammatory and injury-associated proteins.

  PublisherOA PDFDOI

• The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways

  Biomolecules · 2025-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (TFH), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT.

  PublisherOA PDFDOI

• Alpha 1-antitrypsin mitigates salt-sensitive hypertension in juvenile mice by reducing diacylglycerol concentrations and protein kinase C activity in kidney membranes

  Frontiers in Molecular Biosciences · 2025-01-20 · 2 citations

  articleOpen access

  Introduction: Recombinant alpha-1 antitrypsin (AAT) therapy has been shown to have beneficial effects to mitigate the progression of various diseases. Here, we hypothesized that administration of pharmaceutical-grade human AAT (hAAT) is effective in mitigating hypertension induced by salt-loading in juvenile mice by reducing the concentration of diacylglycerols (DAGs) and activity of protein kinase C (PKC) in the kidney. Methods: Four-week old 129Sv mice were salt-loaded to induce hypertension and then administered hAAT or vehicle. Results: Administration of hAAT was found to significantly reduce high blood pressure in both the active and inactive cycles of the 129Sv hypertensive mice. A lipidomic analysis showed decreased concentrations of multiple diacylglycerols in kidney cortex membrane fractions from mice treated with hAAT compared to vehicle. PKC activity was less in the 129Sv mice that received hAAT compared to vehicle. Western blotting and immunohistochemistry analysis showed the density of the sodium-potassium-chloride co-transporter (NKCC2) was significantly reduced in kidney cortex membrane fractions of juvenile mice that received hAAT compared to vehicle. Conclusion: Taken together, this study demonstrates a new protective effect of hAAT in normalizing blood pressure after the development of saltinduced hypertension in juvenile mice in a mechanism involving a decrease in NKCC2 membrane expression, presumably due to decreased levels of DAGs in the plasma membrane and a subsequent decrease in PKC activity.

  PublisherDOI

• The under‐appreciated world of the serpin family of serine proteinase inhibitors

  EMBO Molecular Medicine · 2023 · 33 citations

  • Biology
  • Biochemistry
  • Computational biology

  In the practice of medicine, many fundamental biological pathways that require tight on/off control, such as inflammation and circulatory homeostasis, are regulated by serine proteinases, but we rarely consider the unique protease inhibitors that, in turn, regulate these proteases. The serpins are a family of proteins with a shared tertiary structure, whose members largely act as serine protease inhibitors, found in all forms of life, ranging from viruses, bacteria, and archaea to plants and animals. These proteins represent up to 2-10% of proteins in the human blood and are the third most common protein family.

  PublisherOA PDFDOI

• Targeting proteolytic cleavage of Toll-Like receptors by alpha-1 antitrypsin inhibited dendritic cells activation and function

  The Journal of Immunology · 2022-05-01

  articleSenior author

  Abstract Toll-like receptors (TLRs) on dendritic cells (DC) interact with self-antigens and play a critical role in systemic lupus erythematosus (SLE) pathogenesis. TLR3, TLR7/8, or TLR9 are endosomal receptors that require proteolytic processing in the endolysosome to initiate signaling in response to DNA, single-stranded RNA, and double-stranded RNA. Targeting this proteolytic processing may represent a novel strategy for inhibiting TLR mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on TLRs is not clear. In this study we first tested the effect of hAAT on DCs. We showed that hAAT treatment inhibited TLR7/8 and TLR9 agonists induced DC expressions of CD80, CD86 and MHC-II and significantly reduced the productions of IL-12, IFN-α and CXCL-10. Mechanistically, hAAT lowered the expression of interferon signature genes (MX-I, Isg-15, IRF-7, Il-12p40 and TNF-α). Importantly, western blot analysis showed that hAAT treatment reduced the active form (cleaved) of TLR9 in DCs indicating a novel mechanism of hAAT function in the immune system. Our in vivo studies in mouse models also showed that hAAT attenuated TLR agonist-induced pathogenesis. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways in DCs, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight for clinical application of hAAT.

  PublisherDOI

• Human Alpha 1 Antitrypsin Suppresses NF-κB Activity and Extends Lifespan in Adult Drosophila

  Biomolecules · 2022-09-22 · 2 citations

  articleOpen accessSenior authorCorresponding

  Human alpha 1 antitrypsin (hAAT) is a multifunctional protein that has been shown to have anti-inflammatory and cellular protective properties. While previous studies demonstrated the antiaging potential of hAAT, the mechanism(s) underlying the antiaging effect remain elusive. In this study, we performed a detailed analysis of transcriptomic data that indicated that NF-κB-targeted genes and NF-κB-regulated pathways were selectively inhibited by hAAT treatment. We further showed that the first detectable impact of hAAT treatment was the inhibition of the nuclear activity of NF-κB. Subsequently, hAAT treatment suppressed the mRNA levels of NF-κB-targeted genes, as well as NF-κB itself (P65 and P50), in human senescent cells. Using Drosophila models, we further examined the impact of hAAT on locomotor activity and endurance. Finally, using an adult-specific promotor, we demonstrated that overexpression of hAAT in the late stage of life significantly extended the lifespan of transgenic flies. These results extend the current understanding of the anti-inflammatory function of hAAT.

  PublisherOA PDFDOI

• Human Alpha 1 Antitrypsin Suppresses NF-ĸB Activity and Extends Lifespan in Adult Drosophila

  Research Square · 2022-08-04 · 2 citations

  preprintOpen accessSenior author

  <title>Abstract</title> Human alpha 1 antitrypsin (hAAT) is a multifunctional protein, which has been shown to have anti-inflammatory and cellular protective properties. While previous studies demonstrated the antiaging potential of hAAT, the mechanism(s) underlying the antiaging effect remain elusive. In this study, we performed a detailed analysis of transcriptomic data, which indicated that NF-ĸB-targeted genes and NF-ĸB-regulated-pathways were selectively inhibited by hAAT treatment. We further showed that the first detectable impact of hAAT treatment was the inhibition of the nuclear activity of NF-ĸB. Subsequently, hAAT treatment suppressed the mRNA levels of NF-ĸB targeted genes, as well as NF-ĸB itself (P65 and P50) in human senescent cells. Using <italic>Drosophila</italic> models, we further examined the impact of hAAT on locomotor activity and endurance. Finally, using an adult-specific promotor, we demonstrated that overexpression of hAAT in late stage of life significantly extended the lifespan of transgenic flies. These results extended the current understandings of the anti-inflammation function of hAAT.

  PublisherOA PDFDOI

• Diesel engine calculation of steady state filtration characteristics of metal fibrous felt particulates filter

  Journal of Physics Conference Series · 2022-10-01 · 1 citations

  articleOpen accessCorresponding

  Abstract Metal fibrous felt particulates filter has the advantages of high mechanical strength, long service life, large dust capacity, high filtration accuracy, low resistance loss and high temperature resistance. In order to obtain the influence of structural parameters of metal fibrous felt on the characteristics of steady-state filtration efficiency, the effects of structural parameters of filter material such as porosity, fiber felt thickness and fiber diameter on steady-state capture efficiency under different filtration speeds are theoretically calculated and analyzed by using numerical calculation method. The results show that the structural parameters have an important impact on the steady-state filtration efficiency, which must be controlled within a reasonable range. Reducing the surface filtration speed to less than 0.1m/s can effectively improve the filtration efficiency. This paper provides a theoretical basis for the selection of structural parameters of metal fiber felt filter material, and has important research value.

  PublisherDOI

Recent grants

• NIH Grant P01DK058327

  NIH · $20.7M · 2011

• NIH Grant R21DK062652

  NIH · $290k · 2005

• NIH Grant R21HL079132

  NIH · $359k · 2008

Frequent coauthors

• Terence R. Flotte

  University of Massachusetts Chan Medical School

  48 shared

• Ahmed S. Elshikha

  University of Florida

  37 shared

• Yuanqing Lu

  University of Florida

  34 shared

• Mark A. Atkinson

  University of Florida

  32 shared

• Clive Wasserfall

  University of Florida

  27 shared

• Olga Golubnitschaja

  University of Bonn

  20 shared

• Martha Campbell‐Thompson

  University of Florida

  20 shared

• Thomas J. Conlon

  University of Pennsylvania

  18 shared

Labs

• Department of Cellular and Systems PharmacologyPI

Education

• Ph.D.

  University of Florida