SPECIFIC AIMS (HIDS) The STAIR consortium represents a unique component of the RDCRN focused exclusively on defects associated with sterols and isoprenoids, important structural and intermediary metabolic components in humans. The majority of defects associated with cholesterol dysfunction reside in the distal region of the pathway, while only two disorders, hyper IgD syndrome (HIDS) and severe mevalonic aciduria (MA), reside in the proximal part of the pathway, both associated with mevalonate kinase deficiency (MKD), the enzyme directly proximal to HMG-CoA reductase, the rate-limiting step of cholesterol biosynthesis and the pharmacological target of the statin drugs. Proposed is a longitudinal, prospective clinical and biomarker assessment evaluation of these two disorders based upon the central hypothesis that the phenotypic diversity in MKD is simply a continuum of phenotypic expression.
Aim 1 will correlate longitudinal changes in clinical features of MA and HIDS, evaluating both inter- and intra-individual changes;
Aim 2 will examine innovative surrogate biomarkers in patients with MA and HIDS over time, with the objective of discovering disease pathomechanisms and surrogate endpoints for future trials;
Aim 3 will bank tissue and DNA samples that will provide longitudinal retrospective samples for future genome-wide expression analyses, an exploratory aim (Fig. 1). Rationale: This protocol will generate the first longitudinal evidence into the evolution and pathophysiological determinants of MKD which we believe will shed light on the phenotypic spectrum of this unique disorder. Through definition of disease-specific pathomechanisms we will unmask novel concepts in sterol and isoprenoid metabolism while simultaneously highlighting novel treatment paradigms for patients. Importantly, a comprehensive understanding of the interplay between sterol and isoprenoid production, and the role that early pathway defects play in these interactions, my shed light on therapeutic considerations that could supplement or serve as adjuvant therapies for the statin drugs, especially interventions devoid of the prominent side effects of these drugs. Our three sub-hypotheses include: 1) deficiency in dolichol production in MKD leads to aberrant protein glycosylation and shedding or secretion of IgD which is normally present as membrane-bound immunoglobulin in B lymphocytes;2) dolichol shortage results in aberrant expression of costimulatory B7-glycoprotein expression on various cell types, as seen in the mvk[=/-] mouse model;and 3) altered oxysterol production in MKD exacerbates immune dysfunction and signaling, and contributes to oxidative damage. We propose a prospective, longitudinal biomarker and clinical analyses design for MKD patients (n=8 patients each, MA and HIDS) which will employ exploratory analysis modeling of longitudinal data in order to unmask patterns of systemic variation, in addition to identification of aspects of random variation that may distinguish individual patients. Moreover, we will employ analysis of the """"""""average"""""""" response over time, employing summary statistics such as mean and standard deviation which can reveal whether different groups are changing in a similar or different fashion. State-of-the-art methodology is employed to examine our innovative study outcomes (clinical and biochemical) in an longitudinal fashion. The project PIs (Gibson, Simon) have extensive track-records in HIDS and MA studies, and are thus perfectly positioned to implement this protocol. The significance and impact of our protocol centers on further delineating the control, regulation and disposition of cholesterol and nonsterol isoprenoids, and especially the links between cholesterologenesis, isoprenoid metabolism and autoinflammatory dysfunction. The innovation of our work centers on the opportunity to perform longitudinal studies of both clinical and biochemical importance. Additionally, we believe our studies will inform selected adverse events associated with statin use, since many of these events share similarities to the pathological processes seen in MKD. Finally, our studies will lay the groundwork for new treatment paradigms in MKD patients, in addition to yet-to-be discovered patients with defects in subsequent pathway enzymes, including phosphomevalonate kinase and mevalonate diphosphate decarboxylase, genetic disorders that should present with elevated urinary accumulation of mevalonic acid as seen in MKD. Accordingly, we believe the overall impact of this protocol is exceptionally high.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Krotoski, Danuta
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University of Nebraska Medical Center
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