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Peptide Inhibitors of Human Voltage Gated Proton Channel hHv1 Activity to Reduce Inflammation

Human voltage-gated proton channels (hHv1) are implicated in a wide range of biological responses, including capacitation of sperm and stimulation of the innate immune response. Human sperm undergo a process called capacitation in the female reproductive tract, whereby intracellular pH rises and stimulates a progesterone-induced Ca2+ influx.  Researchers at the University of California, Irvine have discovered that this calcium influx is controlled by albumin activation of Hv1 voltage-gated proton channels.  Albumin activation of hHV1 in neutrophils also supports production and release of reactive oxygen species and protease during the immune respiratory burst.  These findings demonstrating a stimulatory role of albumin in both sperm and neutrophils has led to new therapeutic approaches to fertility and the treatment of inflammatory diseases.

Sialic Acid Inhibitor in Cancer Treatment and Immunotherapy

Researchers at the University of California, Davis have developed a method of inhibiting sialic acid expression which is commonly related to bacterial and viral infections, metastatic cancer, and other pathogenic processes.

Novel Estrogen Receptor ß (ERß) Drugs for the Treatment of Multiple Sclerosis (MS)

Prof. Seema K. Tiwari-Woodruff from the University of California, Riverside, Prof. John Katzellenbogen and colleagues from the University of Illinois have developed novel estrogen receptor β (ERβ) drugs for the treatment of MS. These novel MS drugs are specific for ERβ and have tremendous potential for the treatment of MS as well as other neurodegenerative diseases. In general, estrogens have anti-inflammatory and neuroprotective activities and clinically reduce the severity of MS and other neurodegenerative diseases. The compounds are more superior to other estrogenic drugs due to their specificity for ERβ and lack of undesirable effects such as feminization and increased risk of cancer. Fig 1: Therapeutic treatment with the UCR ERβ ligands began at peak disease (day 17) and was continued daily till day 36. ERβ ligands (blue, and orange) significantly attenuated clinical disease severity compared to vehicle treatment (red).  

Inhibitors of Bromodomain and Extra-Terminal (BET) Family Proteins as Potential Treatments for Drug-Resistant Tumors

Researchers at the University of California, Davis have developed small molecule inhibitors for use in treating drug-resistant tumors – including cancerous tumors.

A Broadly Neutralizing Molecule Against Clostridium Difficile Toxin B

Researchers at UCI have developed a family of recombinant protein therapeutics against Clostridium difficile designed to provide broad-spectrum protection and neutralization against all isoforms of its main toxin, TcdB. These antitoxin molecules feature fragments of TcdB’s human receptors which compete for TcdB binding, significantly improving upon existing antibody therapeutics for Clostridium difficile infections.

Methods of treating systemic lupus erythematosus

Brief description not available

Clearance of Senescent Cells by Activation of the Immune Response

Researchers at UCSF have developed a method to selectively clear senescent cells by stimulating an immune response. Accumulation of senescent cells underlies a number of disease conditions and age-related pathologies. Current approaches to clear this cell type use senolytics, these are small-molecules that induce cell death of the senescent cells. Unfortunately, these compounds are not truly specific and affect other non-pathogenic cells. UCSF researchers eliminate these off-target effects by utilizing the body’s immune system to selectively target senescent cells for clearance. They do this by activation and expansion of certain immune cells. Stimulating the immune system to clear these cells is unprecedented in the field and offers a new therapeutic modality to treat senescence associated conditions. The technology has been fully validated in a laboratory setting.

Insulin Infusion Cannulas with Superior Performance

Researchers at UCI have developed the application of a biocompatible material to insulin infusion devices for Type 1 Diabetes to improve device strength, reduce scar tissue buildup, and increase the efficiency of insulin delivery.

Modulation of Protein Tyrosine Phosphatase Receptor Type A (PTPRA) to Treat Arthritis

Fibroblast-like synoviocytes (FLS) in the intimal lining of the joint synovium control the composition of the synovial fluid and extracellular matrix (ECM) of the joint lining. In rheumatoid arthritis (RA), FLS become aggressive and invasive, contributing to many aspects of RA pathology. FLS produce matrix metalloproteinases (MMPs) that break down the ECM, directly invade and digest the articular cartilage, promote bone erosion, and promote inflammation through secretion of interleukin 6 (IL-6), chemokines, and other inflammatory mediators. FLS are highly sensitive to the inflammatory environment present in rheumatoid joints. Growth factors, especially platelet-derived growvth factor (PDGF), stimulate FLS invasiveness. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF) and interleukin-I (IL-1), enhance FLS aggressiveness, pro-inflammatory features and MMP production. Targeting of molecules that control FLS invasiveness and inflammatory output is being considered an option for development of new therapies for RA.   Many signaling pathways controlling FLS behavior rely upon phosphorylation of proteins on tyrosine residues, which results from the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). We found that a protein (PTPRA) belonging to a novel and currently untapped class of drug targets is present at high levels in cells lining the joints of RA patients, where we believe it promotes the aggressive behavior of these cells in joint inflammation and destruction.

Fusion Protein for Treatment of Inflammatory Diseases

Researchers at the University of California, Davis have developed a plant-based, fusion protein for use in the treatment of inflammatory diseases.

Human-Centered Drug Discovery: A Methodology To Identify And Validate High-Value Therapeutic Targets For Human Diseases

Modeling diseases as networks has helped simplify an otherwise complex web of multi‐cellular processes; however, an exclusive reliance on symmetric relationships in these networks overlooks the existence of disease continuum states and loses information relevant to pathogenesis and for the development of therapeutics. Network‐based analyses severely influenced by symmetric analyses have helped formalize Network Medicine as a field and deliver many successes, but drugs that can predictably re‐set the network in complex multi‐component diseases are yet to emerge.

Novel microbial species that promote fetal tolerogenic immunity

New therapies to prevent the development of asthma and other chronic inflammatory diseases in infants using natural bacterial modulators of fetal immune development.

New Immunomodulatory Compounds

Regulatory T cells (Treg) play a critical role in controlling immune responses, chronic inflammation and autoimmune disease. Integrin activation in CD4+ FoxP3+ Treg is crucial to the maintenance of Treg numbers and function in vivo. Tregs also express high levels of the low affinity IL2 receptor CD25 (IL2Ra, TAC) on their cell surface. One mechanism by which Tregs are thought to limit immune responses is by sequestering the available IL2, effectively starving effectors and leading to peripheral tolerance. Previous work by the inventors showed that activation of integrin adhesion receptors were critical to the functioning and maintenance of peripheral Tregs. The present invention describes antibodies that specifically activate integrins on Tregs but not on conventional T cells. These antibodies promote the proliferation and outgrowth of Tregs but not of conventional T cells in vitro.   Thus, treatment with such antibodies would be expected to ameliorate auto-immunity.

Use of Thiazolidinediones for Treatment of Eosinophilic Esophagitis Pathologic Remodeling

Esophageal inflammatory disorders are gaining increased recognition in both adults and children. One example is eosinophilic esophagitis (EoE), which is an emerging and fast-growing disorder characterized by high levels of eosinophils in the esophagus, as well as esophageal cellular changes such as basal zone hyperplasia and esophageal remodeling that includes fibrosis and smooth muscle dysfunction. These complications can lead to trouble swallowing, strictures,and food impactions. EoE is thought to be provoked, in at least a subset of patients, by food allergies or airborne allergen exposure. EoE diagnosis is often associated with other hypersensitivity disorders, including asthma, rhinitis, and other food and aeroallergen inhalant sensitivities. Diagnosis requires the finding of 15 or more eosinophils per high power field (eos/hpf) within esophageal mucosal biopsies. Although EoE is becoming more frequently diagnosed throughout developing countries, many aspects of the disease remain unclear including its etiology, natural history and optimal therapy. Symptoms of EoE often mimic those of gastroesophageal reflux disease (GERD) and include vomiting, dysphagia, pain and food impaction. In the absence of long-term treatment, up to 70-80% of adults with eosinophilic esophagitis (EoE) may go on to develop esophageal strictures. This disease now is likely to occur in 1 in 1000 people in the population and will have a dramatic effect on the patients’ quality of life. While there are therapies that control inflammation, not all patients respond to these therapies and continue to progress to fibrotic changes. There are currently no medical treatments to directly target esophageal fibrosis.

Use of Gene Therapy to Treat Joint Disease and Synovial Tumors

The National Center for Advancing Translational Sciences and Genetic and Rare Diseases Information Center characterizes Pigmented villonodular synovitis (PVNS) as a rare disease estimated to occur in ~ 5-6 people out of 100,000. This locally invasive tumor most often occurs in younger adults and causes severe damage to joints. The first line of treatment is surgery but at least 50% of patients require multiple surgeries over many years due to re-growth of the tumor.

TRM:CRAMP Knockout Mice In The C57bl/6 Background

The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection.

TRM: Slc7a2/CAT2 KO Mice

CAT2 is a membrane associated protein involved in the cellular uptake of cationic amino acids such as arginine, lysine and ornithine. CAT2 plays a regulatory role in the activation of macrophages. Arginine is a substrate for nitric oxide synthase (NOS) during the production of nitric oxide (NO). The release of NO by inflammatory cells contributes to the progression of diseases such as cancer, arthritis, inflammatory bowel disease, Crohn's disease, and atherosclerosis. CAT2 plays a role in controlling inflammation and IL-17 activation in an injury model of colitis.

Using Bacteria for Gut Health Improvement and Weight Management

Researchers at the University of California, Davis have developed a method of using bacteriocin peptides to reduce gut inflammation, improve gut barrier function, and reduce obesity in humans.

Hv1 Modulators and Uses

Researchers at UCI have engineered a class of Hv1 polypeptide modulators that selectively modulate Hv1 voltage gated channels while leaving other voltage gated channels unaffected. With no Hv1 modulators currently on the market, this class of Hv1 polypeptide modulators could provide solutions in birth control, autoimmune therapies, and tumor reduction.

A New Approach To Treat/Manage Inflammatory Bowel Disease

Researchers at UCI have developed a safe, inexpensive drug for the treatment of inflammatory bowel diseases.

Engineered Biomaterial to Prevent Endothelial Inflammation

Researchers at the University of California, Davis have developed a biocompatible material to mimic the glycocalyx, the natural layer of molecules that coats the outside of endothelial cells. This technology can be used to treat inflammation in diseases characterized by dysfunction in leukocyte-endothelial cell interactions.

Development of Methods to Inhibit IL-1β and IL-18 Production

Macrophages respond to pathogens and tissue damage via pattern recognition receptors (PRR) that sense pathogen (PAMP) or damage (DAMP) associated molecular patterns. NLRP3, a member of the Nod-like receptor (NLR) family that is induced upon macrophage activation, senses cytosolic oxidized mitochondrial DNA (ox-mtDNA) that is generated when activated macrophages are exposed to NLRP3- activating DAMPs, such as ATP, uric acid, or amyloid β, triggers IL-1β and IL-18 production and release. IL-1β and IL-18 are members of the IL-1 family of cytokines representing two of eleven members. As a whole, the IL-1 group of cytokines can induce strong inflammatory signals. Moreover, IL-1β and IL-18 are unique members because they are inactive until undergoing proteasomal cleavage by caspase-1 leading to the formation of active biological forms. Recent work has shown that NLRP3 inflammasome dependent production of IL-1β and IL-18 is involved in the pathogenesis of many devastating diseases, including cancer, Alzheimer’s disease, rheumatoid diseases and cryopyrin-associated periodic syndromes. and autoimmune diseases such as lupus or Still’s diseases. Thus, there exists a need to modulate the production of both IL-1β and IL-18.

Targeting Hyaluronan as an Immunomodulator for Treatment of Inflammatory Diseases

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and has been associated with poor quality of life and frequent complications requiring hospitalization and surgical procedures. Current therapies for IBD typically target neutralization of inflammatory cytokines, blockade of receptors, or inhibition of inflammatory cell functions. Despite current approaches, it is still difficult to control disease severity and maintain quality of life. One important phenotype of IBD that may offer an opportunity for gaining increased understanding of the disease is that up to 40% of individuals with inflammatory diseases of the colon have extra intestinal manifestations. Foremost in these extra intestinal symptoms are skin or oral disorders such as erythema nodosum, pyoderma gangreneosum and aphthous stomatitis. The presence of diseases associated with IBD at sites far from the gut support several hypotheses that IBD is a systemic disorder of circulating bone marrow derived immunocytes, a consequence of dysbiosis of the microbiome or a generalized disorder of epithelial function. Furthermore, appropriate function of the epithelial barrier is necessary to regulate the interactions between microbes and the host and maintain health.

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