Identify molecular targets in T-cells, including novel, co-stimulatory molecules and their downstream effectors, as target candidates for drugs. 
 

• Collaboratively explore the downstream signaling of membrane-bound, co-stimulatory molecules, such as PD-1, for identifying novel molecular targets involved in immune dysfunction.
   
• Design antibodies with unique specificity, which recognize human costimulatory proteins and their mouse homologs.
   
• Develop potential therapeutics that can be studied in mice.
   
• Construct diagnostic and predictive tests for autoimmune disease, based on polymorphism analysis.
   
• Develop novel agonists and antagonists of co-stimulatory molecules that inhibit autoimmune responses, promote anti-tumor immunity, or promote anti-microbial immunity.
   
• Uncover novel agonists and antagonists of co-stimulatory pathways, in partnership with a bioinformatics team.

• Study the role of co-stimulatory T-cell molecules, including the B7/CD28 gene family, particularly the CTLA4/B7, CD28/B7, PD-1/PD-L1/PD-L2, and ICOS/B7h pathways, in controlling T-cell activation, anergy, peripheral tolerance, regional tolerance, autoimmune disease, chronic viral infection, inflammation, and atherosclerosis.
• Research the functional consequences for T-cells of B7-1 binding to both PD-L1 and CD28
• Investigate the phenomenon of T-cell exhaustion in chronic viral infection.
• Devise methods to reinvigorate the T-cell response by blocking the activity of T-cell negative regulators, such as PD-1 or its ligands.
• Explore other aspects PD-1, PD-L1, and their ligands in T-cell biology, including their roles in autoimmune disease, peripheral tolerance, and central tolerance.
• Employ different genetic mouse models as in vivo research tools, to study T-cell co-stimulatory function and model disease, including: T-cell co-stimulatory gene and double gene knockouts; conditional transgenic overexpressors to dissect the function of the T-cell co-stimulatory molecules; and the discovery of new co-stimulatory receptor and ligand binding partners.
   

Dr. Sharpe’s lab uses unique research tools, such as mouse gene knockouts; conditional and tissue-specific transgenic overexpressors for research and drug screening; and mouse disease models, including experimental autoimmune encephalomyelitis (EAE is a model for multiple sclerosis) and systemic lupus erythematosis.

The immune system has a remarkable ability to respond to an incredible variety of microbes, but does not respond to self. The mechanisms that normally protect individuals from infection have the capacity to cause tissue damage and disease, and therefore  immune responses are highly regulated. Dr. Sharpe’s laboratory has made important contributions to the understanding of the mechanisms that regulate the balance between the activation and inhibition of T cell responses. Her laboratory focuses on T cell co-stimulation and its immunoregulatory role in controlling the balance between T cell activation and tolerance.

The laboratory also explores pathways in the B7/CD28 co-stimulatory gene family members, including ICOS and PD-1 and their respective ligands, B7h and PD-L1/PD-L2. Dr. Sharpe’s lab uses a genetic approach of developing novel knockout mouse strains, which lack one or more of the costimulatory receptors and ligands, to better understand the pathways’ functions. Her mouse strain studies have yielded insights into the functions of B7/CD28 gene family members, which play crucial roles in shaping the T-cell response. For example, the lab found that the CTLA-4 receptor was instrumental in ratcheting down the T-cell activation process, an important function for inducing self-tolerance and preventing autoimmunity. The lab’s recent studies have demonstrated the importance of the PD-1 receptor for peripheral tissue tolerance, restraining self-reactive T-cells present in tissues, such as the pancreas.
 

Biological Mechanisms and Pathways

• Adaptive immunity •
• B7 •
• CD28 •
• Costimulatory molecule •
• CTLA-4 •
• Immune tolerance •
• Immunological synapse •
• Immunology •
• Infectious disease •
• Inflammation •
• PD-1 •
• Regional immunity •
• T-cell •
• T-lymphocyte
•  

Diagnostics

• Autoimmune disease
•  

Disease Mechanisms

• AIDS •
• Atherosclerosis •
• Autoimmune disease •
• Chronic viral infection •
• Diabetes •
• Hepatitis •
• HIV •
• Infectious disease •
• Inflammation •
• Organ transplant rejection
•  

Immunology

• Immunology
•  

Infectious Disease

• Chronic viral infection •
• Hepatitis •
• HIV
•  

Research Tools and Instrumentation

• Knockout mouse •
• Transgenic mouse •
• Tumor immunotherapy
•  

Therapeutic Discovery Tools and Assays

• Atherosclerosis
•  

Therapeutics

• Tumor immunotherapy
•