Optimizing biomedical discoveries as an engine of culture change in an academic medical center.

Academic discovery in biomedicine is a growing enterprise with tens of billions of dollars in research funding available to universities and hospitals. Protecting and optimizing the resultant intellectual property is required in order for the discoveries to have an impact on society. To achieve that, institutions must create a multidisciplinary, collaborative system of review and support, and utilize connections to industry partners. In this study, we outline the efforts of Case Western Reserve University, coordinated through its Clinical and Translational Science Collaborative (CTSC), to promote entrepreneurial culture, and achieve goals of product development and startup formation for biomedical and population health discoveries arising from the academic ecosystem in Cleveland. The CTSC Office of Translation and Innovation, with the university's Technology Transfer Office (TTO), helps identify and derisk promising IP while building interdisciplinary project teams to optimize the assets through key preclinical derisking steps. The benefits of coordinating funding across multiple programs, assuring dedicated project management to oversee optimizing the IP, and ensuring training to help improve proposals and encourage an entrepreneurial culture, are discussed in the context of a case study of therapeutic assets, the Council to Advance Human Health. This case study highlights best practices in academic innovation.

Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions.

OBJECTIVE: To determine the role of bone morphogenetic proteins (BMPs) in stimulating glial scar formation in demyelinating lesions of the adult spinal cord. METHODS: The dorsal columns of adult rats were injected with lysolecithin to induce a local demyelinating lesion. Levels of BMP4 and BMP7 proteins were assayed and compared with glial fibrillary acidic protein expression in the injury area. BMP-responsive cells were identified by expression of phosphorylated Smad1/5/8. Cultures of mature spinal cord astrocytes were treated with BMP4, and levels of chondroitin sulphate proteoglycans (CSPGs) were measured. The effect of BMP4 on CSPG gene regulation was determined by real-time polymerase chain reaction for CSPG core proteins. RESULTS: BMP4 and BMP7 increase rapidly at the site of demyelination, and astrocytes surrounding the lesion increase expression of phosphorylated Smad1/5/8. Cultured mature astrocytes respond directly to BMPs with Smad1 translocation to the nucleus, increased phosphorylated Smad1/5/8, and increases in glial fibrillary acidic protein and CSPG expression. BMP treatment also increased CSPG messenger RNA for CSPG core proteins, including aggrecan and neurocan. Increases in CSPG expression in astrocytes by BMPs were blocked by the inhibitor noggin. Injections of BMP4 or BMP7 into the dorsal columns in the absence of demyelination led to increases in CSPG expression. INTERPRETATION: Local increases in BMPs at the site of a demyelinating lesion causes upregulation of gliosis, glial scar formation, and heightened expression of CSPGs such as neurocan and aggrecan that may inhibit remyelination.

Raf-induced effects on the differentiation and apoptosis of skeletal myoblasts are determined by the level of Raf signaling: abrogation of apoptosis by Raf is downstream of caspase 3 activation.

We examined the effect of a constitutively active Raf protein (Raf-CAAX) on the differentiation and the coincident apoptosis of skeletal myoblasts. We found that a low level of Raf signaling leads to accelerated differentiation when compared to parental myoblasts, while a higher level of Raf signaling induces a transformed morphology and abrogates both differentiation and the coincident apoptosis. Raf signaling abrogates apoptosis without blocking the activation of caspase 3 and the subsequent cleavage of caspase 3 substrates. Eliminating the signal from Raf through MEK does not restore the ability to differentiate or to undergo apoptosis in the myoblasts with a high level of Raf signal, nor does it abrogate the accelerated differentiation observed in myoblasts with lower levels of Raf signal. Constitutive signaling through MEK is required, however, to maintain a transformed morphology. These results indicate that the effect of Raf on the differentiation and apoptosis of skeletal myoblasts is dictated by the level of Raf signaling, and that Raf signaling sufficient to abrogate the apoptosis coincident with differentiation does so downstream of caspase 3 signaling.