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Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2004

DESCRIPTION (provided by applicant): The goal of the proposed research is to demonstrate that Inter-alpha serine protease inhibitor proteins (IaIp) are an effective therapy for sepsis. In sepsis, normally high plasma levels of IaIp drop dramatically in

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.69K | Year: 2015

DESCRIPTION provided by applicant Wound healing is an intricately regulated process broadly characterized by phases of inflammation proliferation and remodeling Imbalances in any one of these phases can result in inadequate healing scar formation or in the development of chronic wounds such as diabetic ulcers Diabetic ulcers are responsible for the majority of lower extremity amputations in the world and are among the principal reasons for hospitalization of diabetic patients These chronic wounds are debilitating painful and frequently never completely heal Despite extensive research and product development to improve wound care the clinical standard of care for these lesions has been largely unchanged for decades Inter alpha Inhibitor Proteins IAIP are naturally derived molecules that serve as a crucial component of the bodyandapos s protective defenses in modulating host response to pathological insults Currently these proteins are being developed as a potent therapy to treat acute life threatening diseases such as systemic inflammatory response syndrome SIRS sepsis and Anthrax intoxication and infection in biodefense applications IAIP have been described to play an important role not only in inflammation and angiogenesis but also in the wound healing process Our recent investigations using genetically altered mice deficient in IAIP bikunin knockout mice revealed a dysregulated wound repair process due to disruption of extracellular matrix ECM reorganization Additionally we found that IAIP level is markedly decreased in the wound tissues of diabetic mice compared to non diabetic controls suggesting impaired and depleted IAIP in the diabetic wound IAIP consist of multiple subunit heavy and light chains uniquely linked by glycosaminoglycan While the IAIP light chain also called bikunin inhibits various serine proteases the heavy chains of IAIP form covalent complexes with hyaluronan to allow efficient binding to its receptors such as CD The IAIP heavy chains also known to interact with matrix cellular proteins such as vitronectin fibronectin and tenascin c to promote wound healing In this proposal we would like to develop a novel topical IAIP formulation and obtain proof of concept of efficacy of a localized IAIP treatment approach in three different experimental models of wound healing using IAIP deficient KO monogenetic diabetic and polygenetic TallyHo diabetic mice We hypothesize that IAIP will play a significant role in the wound healing process affecting epidermal regeneration as well as extracellular matrix organization If confirmed this novel topical treatment based on plasma derived IAIP can be translated readily into the clinical use for problematic and chronic wound care The localized immunomodulatory IAIP treatment might also prevent wound complication and super infection making the potential impact of this research immense PUBLIC HEALTH RELEVANCE Problematic wounds such as diabetic ulcers are responsible for the majority of lower extremity amputations in the world and are among the principal reasons for hospitalization of diabetic patients These chronic wounds are debilitating painful and frequently never completely heal In this proposal we will develop a novel topical biological product based on natural proteins extracted from human blood As part of the components in wound healing process these proteins regulate inflammation and promote wound repair process This proposal will advance public health by developing a novel therapeutic strategy for wound care

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 498.06K | Year: 2012

DESCRIPTION (provided by applicant): The primary goal of this proposed research is to develop a rapid point-of-care (POC) test that can be used to identify neonatal sepsis in high-risk infants in a simple, user-friendly and portable device suitable for usein the NICU setting. Since sepsis presents a very serious threat to neonates, there is an urgent need to obtain confirmation as soon as possible. Currently, there are no reliable, POC markers for this life threatening disease. Blood culture results are considered the gold standard for bacterial sepsis, but confirmatory results may not be available until at least 48 hours. In this proposal, we will attemp to develop a quantitative rapid test based on Inter-alpha Inhibitor Proteins (IAIP) that has been recently demonstrated as a valuable biomarker with high sensitivity and specificity (89.5% and 99%, respectively) and a high positive and negative predictive value (85% and 98% respectively) for neonatal sepsis. We hypothesize that endogenous IAIP, as part of the innate immune response, protect against the damaging effects of proteases released during acute systemic inflammation following severe infections, burn, trauma and injury. As a consequence, these proteins are rapidly consumed and excreted in the urine,leading to a rapid decrease in plasma levels. Furthermore, the IAIP level seems to inversely correlate with disease severity and progression, thus, a rapid IAIP test with result that can be obtained within 10- 15 min would be useful as a diagnostic and/ortheranostic marker in neonatal sepsis. The proposed specific aims of the study are: 1) Validation and comparison studies of the predictive value of IAIP alone and with other biomarkers in detecting infants with sepsis and systemic inflammation and 2) Prototype development of a quantitative lateral flow immunoassay (LFIA) for IAIP that can be used to diagnose neonatal sepsis and NEC. As a replacement therapy with plasma derived IAIP has been demonstrated to be effective in experimental models of sepsis and clinical trials in adult septic patients are currently underway, our long-term objective is to study the efficacy of concomitant IAIP treatment in critically ill infants due to suspected sepsis or NEC with low levels of IAIP as revealed by the rapid test.By combining the predictive test and therapeutic replacement of plasma derived IAIP, this novel approach may offer a rational, targeted solution for reducing the morbidity and mortality associated with neonatal sepsis and NEC in infants. Furthermore, an IAIP-based rapid test will provide an objective means for reducing antibiotic overuse in infants with suspected but unproven systemic infection. The potential impact of the proposed research is immense when one considers the serious unmet medical need for infants who suffer from the devastating effects of neonatal sepsis and NEC. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to develop a rapid test that can be used to detect life-threatening conditions such as whole body infection (sepsis and necrotizing enterocolitis) in infants using a simple, user-friendly and portable device suitable fo a bedside testing in the neonatal intensive care unit. The test is based on the level of blood proteins called Inter-alpha Inhibitors that are consumed during the disease. The faster the patient is diagnosed and treated, the better the prognosis and a chance of fewer complications. The potential impact of the proposed research is immense as it will reduce the devastating effects of these diseases.

Threlkeld S.W.,Rhode Island College | Gaudet C.M.,Rhode Island College | La Rue M.E.,Brown University | Dugas E.,Rhode Island College | And 3 more authors.
Experimental Neurology | Year: 2014

Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full term birth related complications. HI injury often results in learning and processing deficits that reflect widespread damage to an extensive range of cortical and sub-cortical brain structures. Further, inflammation has been implicated in the long-term progression and severity of HI injury. Recently, inter-alpha inhibitor proteins (IAIPs) have been shown to attenuate inflammation in models of systemic infection. Importantly, preclinical studies of neonatal HI injury and neuroprotection often focus on single time windows of assessment or single behavioral domains. This approach limits translational validity, given evidence for a diverse spectrum of neurobehavioral deficits that may change across developmental windows following neonatal brain injury. Therefore, the aims of this research were to assess the effects of human IAIPs on early neocortical cell death (72. h post-insult), adult regional brain volume measurements (cerebral cortex, hippocampus, striatum, corpus callosum) and long-term behavioral outcomes in juvenile (P38-50) and adult (P80. +) periods across two independent learning domains (spatial and non-spatial learning), after postnatal day 7 HI injury in rats. Here, for the first time, we show that IAIPs reduce acute neocortical neuronal cell death and improve brain weight outcome 72. h following HI injury in the neonatal rat. Further, these longitudinal studies are the first to show age, task and treatment dependent improvements in behavioral outcome for both spatial and non-spatial learning following systemic administration of IAIPs in neonatal HI injured rats. Finally, results also show sparing of brain regions critical for spatial and non-spatial learning in adult animals treated with IAIPs at the time of injury onset. These data support the proposal that inter-alpha inhibitor proteins may serve as novel therapeutics for brain injury associated with premature birth and/or neonatal brain injury and highlight the importance of assessing multiple ages, brain regions and behavioral domains when investigating experimental treatment efficacy. © 2014 Elsevier Inc. Source

Lazrak A.,University of Alabama at Birmingham | Jurkuvenaite A.,University of Alabama at Birmingham | Ness E.C.,University of Alabama at Birmingham | Zhang S.,University of Alabama at Birmingham | And 7 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2014

Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Intera-inhibitor (IαI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IαI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IαI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl2 currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IαI in ATII cells were accompanied by increased levels of uncleaved (immature) surface a-ENaC. IαI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (ΔF508), or CF transmembrane conductance regulator knockout mice with IαI for 3 hours decreased the open probability of their ENaC channels by 50%. ΔF508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IαI in their BALF. A single intranasal instillation of IαI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IαI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of ΔF508 mice. Copyright © 2014 by the American Thoracic Society. Source

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