Glioblastoma multiforme (GBM) is a highly malignant brain tumor type with 14 months average patient survival, high incidence of recurrence and no effective line of treatment. Genomic analyses became an essential resource to understand the molecular alterations that cause cancer. In the case of GBM, analysis of hundreds of samples produced an extensive transcriptomic map, identified prevalent mutations and defined important tumor drivers. Unfortunately, clinical trials based on these results have not yet delivered positiv outcomes.

DESCRIPTION (provided by applicant) Funds are requested to purchase an Illumina HiSeq 3000 Sequencer for the Genome Sequencing Facility (GSF) of Greehey Children's Cancer Research Institute (GCCRI) at the University of Texas Health Science Center at San Antonio (UTHSCSA). At the present time, high throughput sequencing is conducted on a heavily utilized Illumina HiSeq 2000 sequencer that was purchased in December 2010, and there were no other publicly accessible high-throughput NGS platforms within UTHSCSA and surrounding San Antonio institutions.

Factors in the tumor microenvironment promote immunosuppression that permits tumor escape from immune destruction. Our data show that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumor inflammatory lymphocyte (TIL) infiltrate. PD-L1 is widely expressed in many tumors and is the target of two successful new cancer immunotherapy approaches, but is a poor predictor of treatment efficacy.

T lymphocytes are critical mediators of immunity; however they are continuously lost for a variety of reasons throughout life, and therefore must be replaced. Generation of new T cells is the function of the thymus, and the unique stromal microenvironment in the thymus directs T cell development and the selection of self- tolerant, self-restricted T cell population. Unfortunately, the thymus undergoes a precipitous age-induced atrophy resulting in reduced naÔve T cell production.

Aberrant activation of the B cell receptor (BCR) is an emerging hallmark of mature B cell tumors. The BCR initiates a signaling cascade that activates multiple kinases, including SYK, BTK and PI3K?, leading to engagement of the NF-?B, PI3K/AKT, RAS and MAPK pathways, thus promoting proliferation/survival of B cells. Considering this pro-growth outcome, it is not surprising that malignant B cells hijack this signaling module for their benefit.

Protein and membrane trafficking depends on choreographed reactions which deform membranes and sequentially assemble and disassemble protein complexes. Hsp70s--the ubiquitous chaperones involved in protein folding and many cellular protein processing reactions--function as motors in trafficking processes such as translocation of proteins into ER and mitochondria, and disassembly of the clathrin coats that form around nascent endocytic vesicles.

Bone is a major site for the preferential metastasis by advanced breast cancers. Bone metastases by breast cancers cause deadly complications and there is an unmet need for efficacious intervention with minimal side effect. The majority of previous studies have primarily focused on metastasized cancer cells or tumor supporting bone microenvironments. Here we propose to investigate the intrinsic anti-cancer metastatic potentials of the osteocytes, the most abundant bone cell type in the bone. Connexin (Cx) 43 hemichannels are richly present in osteocytes.

Chlamydia trachomatis infection in urogenital tract, if untreated, can cause severe complications. Due to lack of obvious symptoms, many C. trachomatis-infected individuals are undiagnosed and untreated. Thus, there is an urgent need for an effective anti-C. trachomatis vaccine. Currently, no licensed C. trachomatis vaccine is available, mainly due to lack of knowledge on protective antigens in C. trachomatis. The failure of human trachoma vaccine trials using formalin-fixed whole C.

Tubule atrophy and fibrosis often develop after acute kidney injury (AKI) favoring transition to chronic kidney disease (CKD). The AKI-CKD transition has major implications, but poorly understood. We found that tubules regenerating after AKI often fail to differentiate. Such tubules are growth arrested and atrophic, and exhibit signaling that drives fibrosis. The cause of this pathology is unknown. We obtained three lines of evidence that could explain why recovering tubules become atrophic and profibrotic.

This proposal aims to understand mechanisms underlying B cell activation and dysregulation. It will explore the role of Rab7, a small GTPase that localizes on endosomes, in mediating NF-?B activation in normal B cells upon receptor engagement and in malignant B cells. It will also analyze the effect of Rab7 inhibition, through genetic ablation or small molecule inhibitors, in the prevention of B lymphomagenesis.