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Medical genetics


Charlotte L. Phillips

Associate Professor of Biochemistry


Email:

phillipscl@missouri.edu

Phone:

(573) 882-5122

Lab:

(573) 884-7244

Fax:

(573) 882-5635

Office:

135A Schweitzer Hall

Mailing
Address:

Biochemistry
117 Schweitzer Hall
University of Missouri-Columbia
Columbia, MO 65211

Research
Areas:

Collagen in inherited and acquired diseases of bone and kidney; matrix metalloproteinases; medical genetics.


Educational Background

BS


University of Central Florida

Orlando, Fla.

Biology

PhD


North Carolina State University

Raleigh, N.C.

Biochemistry

Notable Honors and Service

Jane Hickman Teaching Award, 1999
Best PBL Tutor, Block 6 Medical Student Driven Award, 2001
Excellence in Education: Pre-Clinical, Medical Student Affairs Council, 2003
William T. Kemper Fellowship for Teaching Excellence, 2004

National Board Certifications

Clinical Molecular Genetics, American Board of Medical Genetics, 1996


Research Description

To investigate the regulation and structure/function of extracellular matrix to tissue specific expression in the pathogenesis of inherited connective tissue disorders.

Type I collagen, the predominant structural protein in many tissues provides strength to bone and tendon, integrity to skin, major organs and blood vessels, and support for mineralization of bone and teeth. Abnormalities in type I collagen synthesis and structure are associated with several acquired and inherited connective tissue disorders (osteogenesis imperfecta, Ehlers-Danlos Syndrome and osteoporosis). Investigating the pathogenesis of the different inherited connective tissues disorders and identifying the specific mutations in the type I collagen genes gives us insight into the multi-structural/functional roles of type I collagen in different tissues.

Current projects include:

Therapeutic Approach to Improve Bone Quality in Children with Osteogensis Imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder often referred to as brittle bone disease, which is characterized by small stature, reduced bone mineral density and frequent fractures. There is a significant range in clinical severity of the disease. With mild osteogenesis imperfecta the patients are ambulatory, this means they can walk and don’t need a wheelchair. But they do have reduced bone density and an increased fracture frequency relative to normal person (similar to osteoporosis). Patients with severe osteogenesis imperfecta are wheel-chair bound, have very reduced bone mineral densities, long bone deformities, and frequent bone fractures (even with very little trauma). They can have up to 200 fractures in their life time. In addition to their bone fragility and small size osteogenesis imperfecta patients reportedly have muscle weakness.

The only study reported in the literature on muscle strength and exercise tolerance was done on children with mild osteogenesis imperfecta. And the researchers found that the OI children had reduced muscle strength and decreased exercise tolerance relative to healthy age-matched children. But it was unclear, if the reduced muscle strength and decreased exercise tolerance were a consequence of sedentary lifestyles or inherent to their disease.

It is well established that the strength and size of muscle are very important to maintaining bone mineral density and the prevention of fractures. Increased exercise, which increases muscle mass (size) and strength can increase bone mineral density and bone biomechanical integrity. We know that increased muscle mass produces an increase in muscle load (tension) on the bone and the bone responds by increasing its bone mineral density (often its thickness as well) and strength.

Preliminary studies in our laboratory with mice that also have osteogenesis imperfecta (oim mouse) suggest that the reduced muscle size in the mice (similar to that seen in patients) is a reflection of their reduced size (smaller than normal mice). In addition analysis of the oim mouse muscle's ability to contract (measure of muscle strength and quality) suggested that there was no difference in muscle strength from age-matched normal mice.

This is extremely exciting: this suggests that children with osteogenesis imperfecta do not have diseased muscles, but that their reduced strength is probably due to reduced activity and lack of exercise. Further, the significance of this is that we can potentially develop therapeutic exercise strategies which will increase their muscle strength and size that will in turn induce their bones to increase in density and thickness. Their denser and thicker bones should decrease their risk of fracture and ultimately may even allow some who are currently wheelchair bound to become ambulatory (able to stand and walk on their own).

Current physical therapy in osteogenesis imperfecta patients includes swimming. The emphasis of the swimming therapy has been on maintaining mobility of the joints in these patients to help maintain quality of life, minimize contractures and prevent further bone weakness. Families are hesitant to try anything that might increase fracture rate (understandably) and increasing exercise or resistance type training is difficult for families to consider. The potential benefits are significant, but the risks to patients are real and without any data to demonstrate that there is a real potential to improve bone strength families and physicians will remain cautious. It is critical that we first demonstrate the feasibility and potential success of an exercise therapy in an animal model of osteogenesis imperfecta for it to be considered a viable therapy for patients.

In this pilot study we have two specific goals: 1) to confirm that there is not a muscle pathology in the oim mouse, 2) to determine if swimming (non-resistance training) and/or running on a treadmill (resistance training) will increase the muscle mass and bone quality in normal mice, mice with mild OI, and mice with severe OI. In addition we will be able to discern whether different clinical severities respond to specific exercise protocols differently.

Pathogenesis of Type I Collagen Fibrosis in a Renal Disease Mouse Model

In chronic renal disease the progressive accumulation of collagen in the glomerular mesangial matrix is a major pathological consequence, culminating in glomerulosclerosis, and renal failure. The production of excess extracellular matrix (ECM) is believed to result from over compensation of the wound healing response in the glomeruli (filtering unit) of the kidney. Though much is known concerning the initiating events leading to the accumulation of the ECM, very little is known mechanistically about the role of the ECM in the disease process and in how the glomerular mesangial cells respond. Recently, our laboratory identified a novel collagen glomerulopathy (disease of the kidney glomeruli) in the oim mouse model. The oim mouse promises to provide new insight into the regulatory role of type I collagen in the pathogenesis of glomerular renal disease.

Oim mice are unable to synthesize normal type I collagen, referred to as heterotrimeric type I collagen, α1(I)2α2(I), due to a type I collagen mutation that results in their inability to make the α2(I) collagen chains. Therefore oim mice compensate by making an abnormal type I collagen exclusively. They synthesize homotrimeric type I collagen, α1(I)3, which results in deposition of homotrimeric type I collagen in the glomerular mesangium of the kidney (a form of kidney fibrosis). In contrast to intact healthy kidney where no type I collagen is normally present in the glomeruli, collagen deposition and glomerular expansion are common features contributing to progressive renal disease and failure, suggesting that homotrimeric type I collagen may play an important role in the pathogenesis of glomerulosclerosis. Additional studies from other laboratories support this role of homotrimeric type I collagen in renal fibrosis. Researchers in other laboratories have demonstrated that when the glomerular mesangial cells from normal mouse kidney are evaluated in culture (taken out of the kidney and grown in tissue culture) they react like an injured kidney and express homotrimeric type I collagen.

Our long term goal is to understand the molecular mechanisms involved in the ECM deposition and pathogenesis of glomerulosclerosis in order to identify targets for therapeutic interventions. Towards this end we propose to 1) characterize the natural progression of the collagen type I glomerulopathy in oim mice and to correlate pathological findings with disease progression, 2) to determine mechanistically whether type I collagen deposition in the oim glomeruli is a consequence of increased collagen expression or aberrant matrix degradation, and 3) to determine if matrix metalloproteinases (the proteins that normally remove collagen) differentially degrade homotrimeric (mutant) and heterotrimeric (normal) type I collagen.

The oim mouse collagen glomerulopathy provides a novel window for identifying the molecular and pathological mechanisms regulating collagen deposition in renal disease and glomerulosclerosis. With the oim mouse we are able to examine the mechanisms controlling collagen deposition in the absence of the confounding affects of primary renal diseases such diabetic nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, and focal glomerular sclerosis, which lead to secondary glomerulosclerosis. Much of the current treatment for kidney disease is targeted to preventing the initiation of this secondary glomerulosclerosis, because once it has initiated it is very difficult to keep from progressing to renal failure. Thus, the oim mouse provides a unique opportunity to sift out the molecular mechanisms controlling matrix deposition without the confounding effects of other disease processes, and to allow identification of potential targets for novel therapeutic interventions.

Analysis of E1α gene of the branch chain a keto acid dehydrogenase complex in patients with maple syrup urine disease (MSUD).

MSUD is an autosomal recessive metabolic disorder resulting from defects in the branched-chain α-keto acid dehydrogenase complex (BCKAD). BCKAD is a multienzyme complex which catalyzes the oxidative decarboxylation of the α-keto acids derived from leucine, isoleucine and valine. BCKAD is comprised of three catalytic components: branched-chain α-keto acid decarboxlyase (E1; an α2b2 structure), dihydrolipoyl transacylase (E2; 24 identical subunits), and a dihydrolipoyl dehydrogenase (E3; homodimer). MSUD is both genetically heterogenous and clinically heterogeneous. Mutations in E1α, E1b, E2, and E3 have been identified. MSUD is rare in the general worldwide population, 1:200,000. However, in certain Old Order Mennonite communities the incidence of the classic MSUD has been estimated to be 1:176. Clinically, the patients quickly become ketoacidotic, presenting within the first two weeks of life with poor feeding, lethargy, seizures, coma and death if untreated. The defect in the Mennonite patients is known, a Y438N substitution in E1α, and is believed to interfere with E1α and E1b assembly.

Selected Publications

Love-Gregory, L.D., Grasela, J.F., Hillman, R.E., and Phillips, C.L. Evidence of Common Ancestry for the Maple Syrup Urine Disease (MSUD) Y393N Allele in non-Mennonite MSUD patients. Molecular Genetics and Metabolism 75:79-90, 2002.

Phillips C.L., Pfeiffer B.J., Luger A.M., and Franklin, C.L. Novel Collagen Glomerulopathy in a Homotrimeric Type I Collagen Mouse (oim). Kidney International 62:383-391,2002.

Vomund AN, Braddock SR, Krause GF, and Phillips CL. Potential Modifier Role of the R618Q Variant of Proa2(I)collagen in Type I Collagen Fibrillogenesis: In vitro Assembly Analyses. Molecular Genetics and Metabolism 82:144-153, 2004.

Graham J.S., Vomund A.N., Phillips C.L., and Grandbois M. Structural changes in human type I collagen fibrils investigated by force spectroscopy. Experimental Cell Research 299:335-342, 2004.

Pfeiffer, B.J., Franklin, C.L., Hseih, F-H., Bank, R.A., and Phillips, C.L. Alpha 2(I) Collagen Deficient oim Mice Have Altered Biomechanical Integrity, Collagen Content, and Collagen Crosslinking of Their Thoracic Aorta. Matrix Biology 24:451-458, 2005

Wenstrup R.J., Florer J.B., Davidson J.M., Phillips C.L., Pfeiffer B.J., Menezes D.W., Chervoneva, I., and Birk D.E. Murine Model of the Ehlers-Danlos Syndrome: col5a1 Haploinsufficiency Disrupts Collagen Fibril Assembly at Multiple Stages. Journal of Biological Chemistry 281:12888-12895, 2006.

Affiliated with the College of Agriculture, Food and Natural Resources and the School of Medicine


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