Research Areas

The renin-angiotensin system (RAS) has become widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found in several, rather unexpected locations in the body including bone marrow, immune cells and brain. Our research interests are focused on deciphering nontraditional functions of RAS in the biology of these systems. We discovered that angiotensin-converting enzyme 1 (ACE1 or ACE), a key component of the RAS, plays a critical role in myeloid cell immune response. For example, ACE knockout strongly suppressed the response of neutrophils and macrophages to bacterial infections. In contrast, increased ACE activity enhances the response of these cells against a variety of insults, including bacterial infections and tumor growth. Similarly, ACE2, another RAS enzyme, expresses in several tissues including brain and all immune cells. In some cases, ACE2 is known for counterbalancing the effect of ACE1. The current studies are aimed at further characterization of the mechanisms of how RAS affects biology of myeloid-derived cells, including their development, homeostasis and response to the immune challenges.

We aim to develop new cell- or gene-based adoptive immunotherapies for treating infections, cancer and chronic inflammation. Our strategies include genetically engineering myeloid cells for improving their responses to the immune challenges (e.g., through delivering gene-encoding RAS components). Our special interest is in developing human iPSC-engineered super neutrophils (Stem-iNeu) for granulocyte therapy to treat patients with severe neutropenia and with the need to fight off aggressive infections. Development of super macrophages (Stem-iMac) for immunotherapy to treat cancer and chronic diseases is also being studied. Targeted gene delivery using organotrophic (e.g., neurotropic) or immune cell-specific lentiviral vectors is another area that the lab is exploring.

Tumor-associated macrophages (TAMs) display a tumor-supportive (i.e., M2-like) phenotype that prevents the body’s immune system from attacking the tumor. Therefore, re-educating TAMs to a tumor destructive (i.e., immune-supportive, M1-like) phenotype could promote anti-tumor immune response. We discovered that overexpression of C-catalytic domain of angiotensin-converting enzyme (ACE) in macrophages drives them toward a pronounced M1 phenotype with activation of NF-kB and STAT1. These macrophages slow down the growth of melanoma in mice. Our lab is investigating biochemical mechanism of how ACE regulates macrophage polarization and their association with tumor antigen presentation and T-cell activation. We are using a proteomic approach for identifying novel peptide molecules produced by ACE C-catalytic domain that stimulate M1 macrophage polarization, and using them for anti-cancer drug development.

Our group is also exploring the mechanisms of how tumor cells acquire resistance phenotype. We found that deregulation of p53 and survivin protein is associated with the poor prognosis of head-neck squamous cell carcinoma (HNSCC). We have designed and tested multimodality therapy regimens including a combination of chemo-radiotherapies and survivin-targeted gene therapy for better killing of resistance HNSCC cells and tumor control in preclinical studies. We are following these initial observations and asking a more basic question as how survivin and other onco-apoptotic proteins deregulated in resistant and recurrent tumors, with emphasis on understanding the role of noncoding RNAs in inducing oncogenic pathways and aggressive behavior of HNSCC and other solid tumors.

Protein-protein interactions are critical for cellular functioning, and their deregulation is involved in several diseases. Targeting these protein-interacting domains could be a promising approach in drug designing. One such domain, the PDZ domain, is encoded by several proteins of the nervous system; in particular at the postsynaptic density site of neurons where they contribute to signal transduction pathways and neurotransmission. Since PDZ domains have well-defined binding sites, often corresponding to short amino acid motifs at the C-termini of target partner proteins, they provide promising targets for drug discovery. Viruses are masters in manipulating the signaling machinery of the cell they infect. Some of them such as rabies virus, which promotes neuron survival by disrupting peculiar PDZ complexes, can serve as a source of inspiration for designing novel neuroprotective drugs.  

Rabies viruses use two main mechanisms to escape the host defenses: 1) its ability to suppress immune response by killing protective migrating T-cells, and 2) its ability to enter the nervous system without triggering apoptosis of the infected neurons and preserving the integrity of neurites. We identified that rabies virus glycoprotein (RABV G), specifically the C-terminus PDZ binding site (PDZ BS) motif of RABV G, is critical for inducing these mechanisms. Lentiviral expression of RABV G or its PDZ BS increases neurite outgrowth and repairs damaged neutrons. We noted that: 1) RABV G triggers neurite outgrowth similar or even better to that induced by db c-AMP treatment, a classical means to trigger neuritogenesis; 2) protects neurites from chemically induced retraction or oxidative stress; and 3) also permits axon, neurite and dendrite regeneration after wounding in an in vitro model of human neurons NT2N, including motor neurons. Our research interest is to understand the mechanism of how rabies virus escapes from the host immune defense system and activates survival pathways in the host neurons, particularly, the pathways regulated by PDZ-BS-PDZ domain interaction and exploiting knowledge to design small peptide compounds based on viruses PDZ-BS for therapeutic proposes, making the neurons regenerate or protect against neurodegenerative processes, or in contrast, induce apoptosis in neuronal cancer cells.