Status: Filled – Intern: Kruthika Gurukkal
Intern: Kruthika Gurukkal
Faculty Name: peter-king
UAB Department: Neurology
UAB School: Medicine
Campus Address: 545 Civitan
Telephone Number: (205) 934-2120
Email: phking@uabmc.edu or Click to Send E-Mail
For how many summers have you served as a preceptor: 1
CCC Research Area: Neuro-Oncology
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. 2
2. Raji Chellappan
Title of Project: 30PK – Suppression of glioblastoma growth through modulation of RNA regulation in tumor associated microglia and macrophages
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). 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 and others have shown that HuR is a major positive regulator of these mRNAs through binding to the ARE and translocating to the cytoplasm to augment translation. Recently, we demonstrated that deletion of HuR in GAMs suppresses glioma growth and prolongs survival. Key factors that promote tumor growth, including maintenance of BTICs and immunosuppression were attenuated with a concomitant increase in recruitment of anti-tumor effector T cells. This exciting discovery provides strong support for the hypothesis of this application that HuR in GAMs modulates GAM/glioma cell crosstalk to create a microenvironment favorable for tumor progression. A corollary is that altering GAM RNA regulation can create a microenvironment that is detrimental to glioma progression. We propose three specific aims to address this hypothesis: (1) Assess the impact of HuR on molecular networks within GAMs and the cellular constituents of glioma tumors and correlate with tumor phenotype, (2) Assess the impact of HuR KO in GAMs on the immune landscape in the glioma microenvironment, (3) Determine whether HuR deletion in GAMs decreases BTIC maintenance and therapeutic resistance. The long term objective of this proposal 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. The significance of this application extends beyond GBM as HuR is expressed in macrophages associated with other solid tumors such as breast and lung.
Project Status: Already up and running
Location of Project: Birmingham, AL (UAB)
Proposed Start Date: May 18, 2020
Proposed End Date: August 18, 2020
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.
Category of Project: Animal Research
Cancer topic: Brain
Does this project involve human subjects: No
Does this project involve animal subjects: Yes
Duty:
1.
Assist with animal breeding and genotyping
2.
Assist with glioma tumor cell injections in mice and tracking tumor progression by in vivo imaging
3.
Assist with analysis of tumor phenotype by flow cytometry, qPCR ad Western blot
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: Possible
Areas in which the ideal candidates will have experience:
Animal Research, Laboratory Skills, basic knowledge, Molecular Biology
