Faculty

The focus of my research is on nagging, a distributed search paradigm that exploits the speedup anomaly by playing multiple reformulations of the problem—or portions of the problem—against each other. Originally developed within the relatively narrow context of distributed automated deduction, we have recently shown how nagging can be generalized and used to parallelize three other standard search algorithms (i.e., A* search, alpha-beta-minimax game tree search, and the Davis-Putnam search algorithm from the artificial intelligence literature. Our results clearly show, both empirically and analytically, the performance advantage of nagging over partitioning for some search algorithms and problem domains. Aside from performance considerations, we note that nagging holds several additional practical advantages over partitioning; it is intrinsically fault tolerant, naturally load-balancing, requires relatively brief and infrequent interprocessor communication, and is robust in the presence of reasonably large message latencies. These properties contribute directly to nagging's demonstrated scalability, making it particularly well suited for use on geographically-distributed networks of processing elements. More recently, I have begun to work on applications of nagging to two important biological optimization problems, both of which have become the topic of ongoing multidisciplinary collaborations between our laboratory and other University of Iowa faculty in the life sciences. The first involves finding the 'best' three-dimensional conformation of a protein (or portion of a protein) with respect to some model of protein energetics, while The second involves using patterns of heritability to find the 'most likely' location of the DNA mutation responsible for a disease. All of these projects are based on the NICE infrastructure, which is actively under development in our laboratory. My research is supported by the National Science Foundation.

Peroxisome proliferator activated receptors (PPAR's) are ligand activated transcription factors which have a pleiotropic role in many physiological processes. PPARγ is the molecular target of the thiazolidinediones class of drugs which are used to treat patients with non-insulin dependent diabetes mellitus (NIDDM). Endothelial dysfunction, which develops in patients that are diabetic or chronically hypertensive, is thought to contribute to the progression of carotid artery disease, cerebral vascular dysfunction and stroke. PPARγ is expressed in vascular endothelium and smooth muscle and therefore is a potentially important factor in the regulation of vascular function and blood pressure. PPARγ has been reported to inhibit responses to vasoconstrictors such as endothelin, stimulate the release of vasodilators, and increase expression of CuZn-SOD in vascular muscle and endothelium. Importantly, patients carrying dominant negative mutations in PPARγ exhibit early onset type II diabetes and hypertension. Current data suggests that PPARγ exerts a protective effect in the vessel wall and we hypothesize that PPARγ plays an important role in the regulation of vascular function and blood pressure. We are currently testing this hypothesis using a variety of genetic, computational and Bioinformatic tools. We are: 1) using adenoviruses over-expressing wildtype and dominant negative mutations of PPARγ in blood vessels from normotensive and hypertensive mice to test whether they can alter endothelial function, 2) developing novel transgenic mice with expression of the wild-type and dominant negative mutants of PPARγ targeted specifically to vascular muscle and endothelial cells using cell-specific promoters, 3) using microarrays to determine the transcriptional targets of PPARγ, and 4) using computational and Bioinformatic tools to scan genomic sequences for PPARγ response elements (PPRE).

My laboratory is studying the genetic basis of deafness and membranoproliferative glomerulonephritis type 2 (MPGN 2). Hereditary deafness is common. It affects 1:2,000 newborns and accounts for greater than 50% of severe-to-profound childhood deafness. It also affects the elderly. Nearly 50% of octogenarians have difficulty communicating without the use of amplification, and in many, the cause is genetic. Inherited hearing impairment can occur with other co-inherited clinical features to form a recognized phenotype (syndromic hearing loss) or appear in isolation (non-syndromic hearing loss). Non-syndromic hearing loss accounts for approximately 70% of genetic deafness. It is almost exclusively monogenic and is highly heterogeneous, with some estimates of the number of deafness-causing genes exceeding 100. We are studying both syndromic and non-syndromic types of deafness. Projects include gene localization by linkage analysis and homozygosity mapping, mutation screening and detection, a variety of functional studies, and hearing-related research on mouse mutants targeting specific genes by RNAi. Membranoproliferative glomerulonephritis type 2 is also called Dense Deposit Disease (MPGN II/DDD). It causes chronic renal dysfunction that leads to kidney failure and a retinal disease similar to age-related macular degeneration, which is the most common cause of blindness in the elderly. Deficiency of and mutations in complement Factor H (CFH) are associated with development of MPGN II/DDD. Changes in CFH are also associated with another renal disease, atypical hemolytic uremic syndrome, and with age-related macular degeneration. We are studying relationships between the alternative pathway of the complement cascade, the structure of the glomerular basement membrane, and MPGN II/DDD to better understanding the pathophysiology of this disease.