The imperative to invest in science has never been greater

In order to sustain and improve the health of Americans, to ensure our ability to overcome new health challenges, and to realize the economic benefits of a vigorous scientific economy, we encourage our government to implement three actions. First, establish predictable, managed growth in the US scientific enterprise by establishing a sustainable and predictable real annual increase in science funding. This will require additional investments in the proven NIH-university partnership to maintain our world-leading position in biomedical science. Second, preserve the current cadre of well-trained junior scientists, including physician-scientists, and maintain a pipeline of young scientists motivated to innovate and improve health. Third, analyze changing health needs and priorities for health science–related investments in order to address ongoing shifts in population demographics and diseases, opportunities for improved prevention or treatment, and the availability of new scientific tools and disciplines. It is in the nation’s best interests -- for good health, for a robust economy, and for scientific leadership -- to advocate for strong federal support of biomedical science in America’s great research universities. Translation of this science yields enormous benefits to our nation’s health and to the economy

Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease

The primary cilium of renal epithelia acts as a transducer of extracellular stimuli. Polycystin (PC)1 is the protein encoded by the PKD1 gene that is responsible for the most common and severe form of autosomal dominant polycystic kidney disease (ADPKD). PC1 forms a complex with PC2 via their respective carboxy-terminal tails. Both proteins are expressed in the primary cilia. Mutations in either gene affect the normal architecture of renal tubules, giving rise to ADPKD. PC1 has been proposed as a receptor that modulates calcium signals via the PC2 channel protein. The effect of PC1 dosage has been described as the rate-limiting modulator of cystic disease. Reduced levels of PC1 or disruption of the balance in PC1/PC2 level can lead to the clinical features of ADPKD, without complete inactivation. Recent data show that ADPKD resulting from inactivation of polycystins can be markedly slowed if structurally intact cilia are also disrupted at the same time. Despite the fact that no single model or mechanism from these has been able to describe exclusively the pathogenesis of cystic kidney disease, these findings suggest the existence of a novel cilia-dependent, cyst-promoting pathway that is normally repressed by polycystin function. The results enable us to rethink our current understanding of genetics and cilia signaling pathways of ADPKD

Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease

Kidney cysts occur following inactivation of polycystins in otherwise intact cilia or following complete removal of cilia by inactivation of intraflagellar transport-related proteins. We investigated the mechanisms of cyst formation in these two distinct processes by combining conditional inactivation of polycystins with concomitant ablation of cilia in developing and adult kidney and liver. We found that loss of intact cilia suppressed cyst growth following inactivation of polycystins and that the severity of cystic disease was directly related to the length of time between the initial loss of the polycystin proteins and the subsequent involution of cilia. This cilia-dependent cyst growth was not explained by activation of the MAPK/ERK, mTOR or cAMP pathways and is likely to be distinct from the mechanism of cyst growth following complete loss of cilia. These data establish the existence of a new pathway defined by polycystin-dependent inhibition and cilia-dependent activation that promotes rapid cyst growth

Small-Molecule CFTR Inhibitors Slow Cyst Growth in Polycystic Kidney Disease

Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTRinh-172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by >80% in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP–containing medium. Subcutaneous delivery of tetrazolo-CFTRinh-172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of >3 μM in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD

Triptolide Reduces Cystogenesis in a Model of ADPKD

Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an attractive therapeutic strategy has been to target the hyperproliferative nature of the disease. We previously demonstrated that the small molecule triptolide induces cellular calcium release through a polycystin-2–dependent pathway, arrests Pkd1−/− cell growth, and reduces cystic burden in Pkd1−/− embryonic mice. To assess cyst progression in neonates, we used the kidney-specific Pkd1flox/−;Ksp-Cre mouse model of autosomal dominant polycystic kidney disease, in which the burden of cysts is negligible at birth but then progresses rapidly over days. The number, size, and proliferation rate of cysts were examined. Treatment with triptolide significantly improved renal function at postnatal day 8 by inhibition of the early phases of cyst growth. Because the proliferative index of kidney epithelium in neonates versus adults is significantly different, future studies will need to address whether triptolide delays or reduces cyst progression in the Pkd1 adult model