Research in the Rana Lab
The human immune system is a complex network of cells, tissues, and organs that work together to defend the body against harmful invaders, such as pathogens (bacteria, viruses, fungi, and parasites) and other foreign substances. There are several key mechanisms and components of the immune system that play essential roles in protecting the body including innate and adaptive immunity, antibodies, B cells, T cells, memory cells, phagocytosis, inflammatory responses, and immune tolerance. These mechanisms work together to maintain a balance between protecting the body from harmful invaders and avoiding harmful immune responses against the body’s own tissues. The immune system is a highly regulated and sophisticated defense system that plays a crucial role in maintaining health and combating infections. The immune system also plays a critical role in maintaining the body’s internal homeostasis by eliminating damaged or abnormal cells, such as cancer cells.
Our lab is pursuing the following projects at the interface of RNA and immunobiology.
RNA-based mechanisms regulating innate and adaptive arms of the immune system.
Effects of RNA viruses such as HIV and SARS viruses on various immune components and organs. One key aspect of the development of AIDS in HIV-infected individuals is collapse of the immune system, resulting in an inability to clear infection. However, it is not clear how HIV induces the reprogramming of immune cell populations that culminates in exhaustion. We are currently deciphering the molecular events underlying T cell exhaustion in diverse subsets of HIV-infected individuals.
Impact of the environment, aging, and disease states on immune system.
Design of new mRNA vaccines for long-term immunity against pathogens and potentially cancers.
What is the mechanism of resistance and how can we sensitize tumors refractory to current immunotherapies? The recent success of immune checkpoint therapies has transformed our approach to cancer treatment and has galvanized hopes that cures for many types of cancer and, potentially, other diseases are on the horizon. Despite the success of FDA-approved biological therapies targeting CTLA-4 and the PD-L1/PD-1 checkpoints in some cancers, many patients do not respond, and the tumors are able to escape therapy. Therefore, we are investigating the fundamental mechanisms that determine whether the host immune system undergoes immune exhaustion leading to tumor evasion or mounts a durable immune response during immunotherapy to various cancers.
The human brain is one of the most complex and fascinating organs in the human body. It plays a central role in controlling and coordinating various bodily functions and processes, as well as in enabling conscious thought, emotions, and complex behaviors. Different regions of the brain are responsible for specific functions. The brain can be affected by aging and various neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and stroke, which can result in cognitive and motor deficits. In addition, viral infections and substance use can also alter brain structure and functions. Recently, researchers have performed single cell sequencing studies to gain insights into the diversity and function of individual cells in various regions of human brain. It is estimated that Brain contains about 3,000 types of cells. These studies provide a great framework for future investigations to understand brain biology and disease pathology as well as risks.
People living with HIV (PLWH) are at the higher risk for impaired cognitive functions due to higher use of legal and illegal opioids that could affect their immune functions and exacerbate CNS (central nervous system) impairment. However, little is known about the HIV harboring cell types in brain, effect of therapy on specific CNS cell types, and the modification of brain functions by opioid use. We have established an NIH funded new research center dedicated to studying how HIV and opioids affect the human brain. By studying the ways HIV infection and opioid use modulate the brain genetically and epigenetically at single cell resolution, our research center aims to address critical public health issues and reshape our understanding of nervous system biology. These results can enhance understanding of the damage caused by chemical exposure, inflammation, aging, and infections from other RNA viruses such as SARS, and help researchers navigate the multifaceted functionality of microglia. The center plans to map multiple regions of the human brain, making way for the discovery of new genes and pathways. The project will analyze more than 100 human brains, followed by validation in animal models, including non-human primates. The results of these single-cell studies are expected to generate novel insights into the transcriptomic and epigenetic landscapes of the CNS.
As a translational research lab, a crucially important aspect of our work is to design and develop innovative therapies based on our research findings. The projects outlined above will undoubtedly identify fundamental processes that regulate the immune system in physiological and pathological situations. The knowledge gained and technologies generated during these studies could provide new opportunities to develop novel ‘personalized medicines’ such as disease-specific interventions, as well as therapies with broader uses such as small molecule, stabilized RNAs therapies, and mRNA vaccines.
RNA epigenetics or epitranscriptomics is an emerging field focused on nucleotide modifications in RNA. One such modification is N6-methylation of adenosine (m6A), which plays important roles in regulating RNA metabolism and gene expression. We are interested in understanding how RNA modifications affect the immune system during viral infections and in the development of cancer. We have identified small molecule inhibitors of various enzymes involved in RNA methylation/demethylation process and modified RNA binding proteins. These drug candidates are effective in vivo and being developed for future clinical trials for targeted molecular monotherapies or as enhancers of immunotherapies. In addition, we have developed small-molecule inhibitors of protein tyrosine phosphatase non-receptor type 2 (PTPN2) that may have clinical utility as sensitizing agents for immunotherapy-resistant cancers such as melanoma and CRC.
We and our collaborators currently have projects ongoing in vaccine design, CRC and glioblastoma, HIV/AIDS, SARS viruses, neurodegenerative disease, drug addiction, cancer immunotherapy, and regenerative medicine.
We employ multidisciplinary approaches involving chemistry and biology and, as part of our commitment to translational research, we routinely collaborate with clinicians, pharmacologists, and engineers. Some examples of these technologies include:
Generation of patient-specific 3D organoids modeling viral infections and cancer.
Stem cell programming using small molecules, RNAs, and non-integrating vectors.
Structure-based drug design and medicinal chemistry.
Drug formulation and stability in vivo.
RNA and small molecule delivery.
Lipid-nano particle design, synthesis, and applications.