Biomedical subjects

Jeffrey R Gingrich

Publications and source records attributed to Jeffrey R Gingrich.

6 recordsLinked to original sources

PubMed2004

Src in synaptic transmission and plasticity.

In the central nervous system (CNS), Src and other Src family kinases are widely expressed and are abundant in neurons. Src has been implicated in proliferation and differentiation during the development of the CNS. But Src is highly expressed in fully differentiated neurons in the developed CNS, implying additional functions of this kinase. Over the past decade, a large body of evidence has accumulated showing that a main function of Src is to upregulate the activity of N-methyl-D-aspartate (NMDA) receptors and other ion channels. NMDA receptors (NMDARs) are a principal subtype of glutamate receptors, which mediate fast excitatory transmission at most central synapses. In this review, we focus on Src as a regulator of NMDARs and on the role of Src in NMDAR-dependent synaptic plasticity. We also describe recent studies that give insights into the regulation of Src itself at glutamatergic synapses. By upregulating the function of NMDARs, Src gates the production of NMDAR-dependent synaptic potentiation and plasticity. Thus, Src may be critical for processes underlying physiological plasticity, including learning and memory, and pathological plasticity, such as pain and epilepsy.

Animals↗

PubMed2004

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2.

Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein-protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling.

Animals↗

PubMed2003

Prostate-specific expression of p53(R172L) differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival.

Loss of heterozygosity or mutation at the p53 tumor suppressor gene locus is frequently associated with advanced human prostate cancer. Hence, replacement p53 gene therapy may prove to be efficacious for this disease. While many mutations result in p53 molecules with oncogenic properties, other variants may possess wild-type properties with increased tumor suppressor activity. We have chosen to investigate the activity of a naturally occurring variant p53 molecule, p53(R172L), carrying an arginine-to-leucine mutation at codon 172. We demonstrate that p53(R172L) can differentially activate expression of genes involved in cell cycle control and apoptosis in vitro. Transgenic mice expressing a subphysiological level of a p53(R172L) minigene (PB-p53(R172L)) in the prostate epithelium were generated and bred to the transgenic adenocarcinoma mouse prostate (TRAMP) model of prostate cancer. While PB-p53(R172L) transgenic mice developed normally with no detectable prostate gland phenotype, we observed a significant increase in the apoptotic index in the prostate glands of TRAMP x PB-p53(R172L) F1 mice. We noted an increase in the expression of Bax in the bigenic mice concomitant with the reduced incidence and rate of tumor growth and increased survival. While low-level expression of the p53(R172L) variant had no obvious influence on normal prostate tissue, it was able to significantly inhibit prostate cancer progression in the context of a genetically predisposed model system. This suggests that additional tumor-related events specifically influence the ability of the variant p53(R172L) molecule to inhibit tumor growth. These studies support gene therapy strategies employing specific p53 variants.

Adenocarcinoma↗

PubMed2002

Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice.

OBJECTIVES: To investigate the effects of flaxseed supplementation on prostatic neoplasia in the transgenic adenocarcinoma mouse prostate (TRAMP) model. METHODS: A total of 135 male TRAMP mice 5 to 6 weeks old were randomized to a control group (AIN-76A diet) or an experimental group (AIN-76A diet plus 5% flaxseed by weight). One half of the mice in each group were treated for 20 weeks and the remainder for 30 weeks. At autopsy, urogenital tissues (four prostatic lobes, seminal vesicles, and emptied bladder), lungs, lymph nodes, and grossly abnormal tissues were collected for histologic evaluation. RESULTS: Of the control mice, 100% developed prostate cancer versus 97% of the mice in the flaxseed group. The tumor/urogenital weight was 3.6 +/- 0.4 g in the controls versus 1.9 +/- 0.2 g in the flaxseed-treated mice (P = 0.0005). At 20 weeks, no significant difference in tumor grade was seen between the two groups; however, at 30 weeks, the flaxseed-treated mice had significantly less aggressive tumors than did the controls (P = 0.01). The prevalence of lung and lymph node metastases was 13% and 16%, respectively, in the control mice versus 5% and 12%, respectively, in the experimental group (difference not significant). After 20 weeks of treatment, cellular proliferation (Ki-67) differed significantly between the control and experimental groups (38.1 +/- 2.03 versus 26.2 +/- 2.03; P <0.0001), and the apoptotic index (deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling) was 1.45 +/- 0.14 versus 3.3 +/- 0.31 (P <0.0001). Similar differences were seen after 30 weeks of treatment. CONCLUSIONS: A diet supplemented with 5% flaxseed inhibits the growth and development of prostate cancer in the TRAMP model.

Animals↗

PubMed2002

Prostate cancer gene therapy.

Numerous gene therapy trials in the United States and throughout the world using various strategies are in progress for the treatment of locally advanced and metastatic prostate cancer. Although vector technology advances at a rapid pace, progress in elucidating the molecular pathways critical for the development and progression of prostate cancer has been slower and more deliberate. Thus far, prostate gene therapy appears to be safe and well tolerated. Through these early clinical trials, the safety and efficacy of gene therapy alone or in combination with more conventional therapy as a basis for the treatment of prostate cancer will ultimately be determined.

Adenoviridae↗

PubMed2002

Transrectal gene therapy of the prostate in the canine model.

Direct transrectal delivery of therapeutic genes utilizing adenoviral vectors for advanced prostate cancer may offer effective treatment at the molecular level. Large animal models to assess feasibility and the intraprostatic and systemic dissemination patterns of these vectors have not been reported. For these studies, a replication-deficient (E1(-)/E3(-)) recombinant adenovirus (AdRSVlacZ) expressing bacterial beta-galactosidase (beta-gal) was delivered under transrectal ultrasound guidance. Two prostate biopsies, followed by concurrent injection of 4.8 x 10(9) pfu of the adenoviral vector divided into either 1 or 2 mL of diluent, were performed (n=4). Swabs of the rectum, sputum, and urine were collected and after 72 hours, the animals were sacrificed. Specimens were assayed for the presence of virus and beta-gal activity. Rectal swabs were transiently positive, whereas urine and sputum samples showed no detectable vector throughout the experiment. Beta-gal activity was observed at the prostate injection sites with detectable activity noted up to 7.5 mm away from the injection site. Systemic dissemination was observed regardless of the injected volume. In conclusion, transrectal prostate biopsy with concurrent prostate injection is a feasible method to deliver therapeutic adenoviral vectors for the treatment of prostate cancer; however, systemic distribution and temporary rectal shedding of virus should be anticipated.

Adenoviridae↗