42PK – RNA regulator tristetraprolin in macrophages and its role in promoting glioblastoma progression through modulation of the tumor microenvironment

Status: Available
Faculty Name: peter-h-king
Primary Faculty Appointment: UAB
UAB/HA Department: Neurology
Campus Address: 545 Civitan
Telephone Number: (120) 593-4212
Email: phking@uabmc.edu or Click to Send E-Mail
For how many summers have you served as a preceptor: 1
CCC Research Area: Cancer Biology & Immunology
Number of hours per week that the preceptor will personally supervise or work with the intern: 3
Other faculty, staff, or graduate students who may help to supervise the intern:
1. Peter King
2. Peter King
Title of Project: 42PK – RNA regulator tristetraprolin in macrophages and its role in promoting glioblastoma progression through modulation of the tumor microenvironment
Project Description:

Glioblastoma (GBM) is the most common central nervous system malignancy and is treatment resistant with a median survival of only 15 months. Treatment resistance centers on the tumor’s remarkable ability to manipulate the microenvironment in which it exists, including suppression of anti-tumor immune responses and induction of factors that support maintenance of the tumor itself, including the therapy resistant brain tumor initiating cells (BTICs) also known as glioma stem cells. Major facilitators of these tumor promoting pathways are glioma-associated microglia and macrophages (GAMs) which comprise 30-50% of the cellular content of GBM. Through crosstalk with glioma cells, the molecular signature of GAMs is shaped to promote tumor progression through the production of cytokines such as IL-6, TGF-β, and VEGF which sustain BTICs and promote angiogenesis and invasion or through membrane-based proteins like PD-L1 which suppress anti-tumor T cell responses. A common regulatory thread for many of these GAM-derived factors is at the mRNA level where AU-rich elements (ARE) in the 3’ untranslated region (UTR) modulate mRNA stability, translational efficiency, and ultimately protein expression. We have recently determined that tristetraprolin (TTP), an RNA binding protein that binds to AREs, is highly expressed in GAMs, especially in perivascular niches where BTICs reside. We hypothesize that TTP modulates the expression of key factors that promote tumor growth, including maintenance of BTICs, immunosuppression, and treatment resistance. We have a TTP knockout mouse (specifically for GAMs) that will be the focus of this project to determine its role in GBM progression. The project will involve in vitro cell culture experiments with glioma cells and in vivo intracranial tumor models using the TTP knockout mouse. The summer student will learn a wide range or experimental techniques and approaches as well as the opportunity to work with the Neurooncology research group. Our long term objective is to gain a mechanistic understanding of how ARE-mediated post-transcriptional regulation in GAMs modulates GBM growth such that new therapies can be developed. The immunosuppressive microenvironment in GBM, for example, remains a major impediment to successful immunotherapies such as checkpoint inhibitors and CAR-T. The innovation of this proposal is its investigation of post-transcriptional regulation as a novel pathway in GAMs that is critical for glioma/GAM crosstalk.

Project Status: Already up and running
Location of Project: Birmingham, AL (UAB)
Proposed Start Date: May 3, 2021
Proposed End Date: August 27, 2021
Expected work schedule for intern: Not very flexible, intern MUST be at work on certain days of the week and at certain times of the day (as may be necessary to interview patients, attend lab meetings, process samples, etc.) and should contribute full-time effort.
Number of days that the student will be expected to come physically to UAB:
More than 1 day per week (prior to start of the internship, gain appropriate waivers and approvals for the student to be on site)
Category of Project: Animal Research
Cancer topic: Brain
Does this project involve human subjects: No
Does this project involve animal subjects: Yes

Assist with working with genetic knockout mouse models–breeding, genotyping, intracranial cancer inductions and imaging


Assist with tissue preparation and immunohistochemistry and imaging


assist with biochemical assays including western blots, qPCR, ELISA

Preceptor will provide intern with access to the following: Office or desk space, Laboratory work bench space, Supplies needed to complete project, Equipment needed to complete project
Likelihood that intern will be included as an author on one or more publications related to this summer research project: Very likely
Areas in which the ideal candidates will have experience: Animal Research, Infectious agents and cancer, Molecular Biology, Pathology